Am J Cancer Res 2018;8(6):916-931 www.ajcr.us /ISSN:2156-6976/ajcr0080015

Review Article receptor 1 in cancer: a new sight for cancer therapy

Ying Shen1,2, Xin Li1,2, Dandan Dong1,2, Bin Zhang1,2, Yanru Xue1,2, Peng Shang2,3

1School of Life Science, Northwestern Polytechnical University, Xi’an 710072, Shaanxi, China; 2Research and De- velopment Institute in Shenzhen, Northwestern Polytechnical University, Shenzhen 518057, China; 3Key Labora- tory for Space Bioscience and Biotechnology, Institute of Special Environment Biophysics, School of Life Science, Northwestern Polytechnical University, Xi’an 710072, Shaanxi, China Received May 21, 2018; Accepted May 29, 2018; Epub June 1, 2018; Published June 15, 2018

Abstract: Iron as an important element plays crucial roles in various physiological and pathological processes. Iron behaves in systemic and cellular two levels that usually are in balance conditions. The disorders of the iron metabolism balances relate with many kinds of diseases including Alzheimer’s disease, osteoporosis and various cancers. In systemic iron metabolism that is regulated by - axis, plasma iron is bound with transferrin (TF) which has two high-affinity binding sites for ferric iron. The generic cellular iron metabolism consists of iron intake, utilization and efflux. During the iron intake process in generic cells, transferrin receptors (TFRs) act as the most important receptor mediated controls. TFR1 and TFR2 are two subtypes of TFRs those bind with iron-transferrin complex to facilitate iron into cells. TFR1 is ubiquitously expressed on the surfaces of generic cells, whereas TFR2 is specially expressed in liver cells. TFR1 has attracted more attention than TFR2 by having diverse functions in both invertebrates and vertebrates. Recently reports showed that TFR1 involved in many kinds of diseases including anemia, neurodegenerative diseases and cancers. Most importantly, TFR1 has been verified to be abnormally expressed in various cancers. Some experimental and clinical drugs and targeting TFR1 have showed strong anti-tumor effects, herein TFR1 probably become a potential molecular target for diagnosis and treatment for cancer therapy. This paper reviewed the research progresses of the roles of TFR1 in the tumorigenesis and cancer progression, the regulations of TFR1, and the therapeutic effects of targeting TFR1 on many kinds of cancers.

Keywords: Iron, TFR1, TFRC, cancer, cancer targeting drugs

Introduction metabolism has been reported the close relat- ed to cancer progression [20-22]. Disorders Iron as an important element plays crucial roles of iron metabolism, especially excessive iron in various physiological and pathological pro- acquisition and retention, can induce tumori- cesses. In all kinds of mammalian cells, iron is genesis and cancer’s growth as well [23, 24]. indispensable to cell growth and division [1, 2], However, high concentration of intracellular and it predominantly controls the formation of iron can make cells in extremely oxidative heme- and iron-containing participat- stress and may induce tumor death. As a no- ing in oxygen transport [3-5], energy metabo- vel form of regulated cell death, ferroptosis is lism [6-8], neurotransmitter generation and typified by lipid peroxidation and relies on iron release [9, 10], synthesis of DNA [11-13], colla- and reactive oxygen species (ROS). Ferroptosis gen and steroid hormones [14-16], nonspecific is morphologically and biochemically different resistance, etc. [17]. However, iron concentra- from other known types of cell death [25, 26]. tion must be strictly controlled, as iron is Thus, whether iron deprivation or induced iron involved in the generation of free radicals in overload in tumor cells can inhibit tumor growth cells [18], a process leading to damage of bio- and cause tumor cell death. A variety of stra- molecules (proteins, lipids, nucleic acids) and tegies for antitumor therapies have been de- in the progression of oxidative stress [19]. Iron signed to target intracellular iron [27, 28], The review of TFR1 in cancer

Table 1. involved in the regulation of lar weight of TFR as a homodimer is 180 kDa TFR1 [42]. Each monomer contains a TF-binding Regulation Reference C-terminal domain, a short N-terminal domain and a single transmembrane domain [33]. CREBBP Activation [56] Transferrin receptors have two subtypes, trans- EP300 [57] ferrin receptor 1 (TFR1) and transferrin recep- HIF-1A [58] tor 2 (TFR2). TFR1 is a homodimeric type II ARNT [59] transmembrane glycoprotein that is express- c-myc [38] ed ubiquitously on the surfaces of most cells c-ETS-1 DNA binding [60] while another member of TFRs, TFR2 is mainly c-Jun [60] expressed in the liver [43, 44]. HIF-1α [61, 62] ATF-1 [63] After TF was discovered as the iron source for immature red blood cells synthesizing hemo- CREB1 Inhibition [63] globin, TFR1 was first considered as a cell sur- face receptor by which TF delivered iron to cells including utilization of 1 [45]. Mammalian TFR1 comprises 760 residue (TFR1)-mediated cytotoxic drug conjugates and subunits that can be divided into a globular iron chelators. As a membrane regulat- extracellular region, a hydrophobic intramem- ing iron import [29, 30], TFR1 is a member of branous region and the remaining residues the TFR family that shows nanomolar affinity to within the cytoplasm [33]. Consisting of two transferrin (TF) bound to Fe (III) [31]. The com- monomers, TFR1 is linked by two disulfide plex of TF-TFR1 is internalized through endocy- bridges, forming a 190 kDa molecule. It is a tosis mediated by clathrin, and Fe (III) is disas- gatekeeper which regulates iron uptake [46]. sociated from TF when pH decreases to 5.5. At Except for mature red cells, almost all cells this pH, apotransferrin and TFR1 are still asso- have TFRs on their surfaces, being most abun- ciated and recycled to cell surface with physio- dant in the placenta, erythron and liver [38]. logical pH, so the former is released [32, 33]. Human TFR1 has three N-linked and one Iron uptake by transferrin receptor is the most O-linked oligosaccharide. Appropriate folding important way for cancer cells to absorb iron, and transport of this protein to cell surface are thus accumulating evidence has proven that significantly affected by N-linked glycosylation TFR1 participated in tumor onset and progres- [33]. sion, and its expression was dysregulated sig- nificantly in many cancers [34, 35]. The rela- TFR1 expressions are delicately regulated at tionship between TFR1 and cancers has been many levels, and several genes are involved in revealed, rendering TFR1 a valuable pharma- the regulation of TFR1 (Table 1). Intracellular ceutical target for intervening with cancers [36- iron concentration regulates the TFR gene post- 39]. Based on these reported studies, in this transcriptional regulation by binding iron-regu- review will summarize the regulatory effects of latory proteins 1 and 2 (IRP1 and IRP2) to the TFR1 on tumorigenesis, and the potential ther- iron response elements in the 5’-untranslated apeutic effects of targeting TFR1 on cancers. region of TFR transcript [45, 47]. IRPs are acti- vated by the deprivation of cellular iron, which Biological functions and regulations of trans- is inhibited through iron repletion [48]. IRP ferrin receptors activities can be regulated by other iron-inde- pendent effectors such as inflammation [49], Transferrin receptors (TFRs) encoded by TFRC oxidative stress [50], hypoxia and xenobiotics is a membrane glycoprotein, which can import [51], or such stimuli under pathophysiological iron by binding a plasma glycoprotein, transfer- conditions [38, 52]. Hypoxia induces the tran- rin (TF) [40]. TF was first referred to as serum scription of TFR1 gene by binding hypoxia-in- protein, with two specific sites binding Fe (III), ducible factors (HIFs) to specific promoter ele- so it is an iron source for synthesizing hemoglo- ments [53]. This process can also be activated bin. Meanwhile, TF-bound iron undergoes cel- by an oncogenic transcription factor c-Myc [38]. lular uptake requiring interaction between this Thirdly, HFE is implicated in the pathogenesis protein and a specific TFR [33, 41]. The molecu- of disordered toxic and progressive iron over-

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Figure 1. Regulation of TFRC transcription. Oxidative stress, inflammation and hypoxia induce HIF expression. HIF induces binding of IRP1 and IRP2. Binding of IRP1 and IRP2 promotes TFRC transcription. C-Jun, C-Myc and cyclin D expressions also induce TFRC transcription. Meanwhile, CREBBP and EP300 are activated to promote TFRC expres- sion. Moreover, ATF-1, CREB1, c-Ets-1 and HIF-1alpha influence the transcription of TFRC by binding DNA. load, i.e. hereditary hemochromatosis [54]. It tastasis are promoted by others [74, 75]. The competes for binding receptor with TF, thus hin- key roles of transferrin receptors (TFRs) in con- dering iron uptake [55]. In addition to the com- trolling the above processes have been well pounds mediating TFR1 regulation mentioned demonstrated over the last decade. TFR1 par- above, its transcription is also influenced by ticipating in tumor progression is abundantly some other transcription factors like CREB1 expressed in liver, breast, lung and colon can- and c-Jun [56] (Figure 1). cer cells [76-79]. Immunohistochemical find- ings of TFRC in various tumor tissues showed and cancer most cancers displayed moderate to strong cytoplasmic positivity. Carcinoid, prostate and The transformation of normal cells into tumo- testicular cancer was negative from The Human rigenic ones and tumor progression involve Protein Atlas [80]. Although the effects of TFRs complicated processes which are still largely on cancer pathophysiology have been studied, unknown. The changes mainly result from accu- the expressions of TFR1 in different cancers mulated mutations of some key genes or pro- are inconsistent and the mechanisms by which teins [64, 65], thus damaging the balances of TFR1 participates in tumor progression remain tumor cells growth [66], proliferation [67], elusive. death [68], gene transcription [69] and angio- genesis [70]. Tumor cells’ proliferation is en- Given that TFR1 is abnormally expressed in hanced and apoptosis is inhibited by some of various cancers (Figure 2A, 2B), it definitely the essential signaling pathways varied upon affects cancer cells’ proliferation [81], migra- tumorigenesis [71-73], while invasion and me- tion [82], invasion [83], apoptosis and metasta-

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Figure 2. Location of TFR1 in three cancer cell lines. Immunofluorescence analysis of TFR1 in A431, U2OS and U251 MG was obtained from The Human Protein Atlas database. TFR1 (Green fluorescence) expressed in vesicles (A), endosomes and (B). sis [76, 84]. Accordingly, several examples played a negative role in the prognosis of glio- showed the regulatory effects of abnormal ma [86]. TFR1 expression on the biological behaviors of cancers (Figure 3). By using the univariate Cox regression model, Yu et al. assessed the prognostic values of Transferrin receptor 1 in cancer genes in two independent datasets of glioblas- toma multiforme (GBM). TFR1 was highly ex- TFR1 participates in regulating the physiology pressed at the early stage. Besides being relat- of glioma cells and the progression of brain ed with clinical outcomes, TFR1 also affected cancer. Rosager et al. reported that TFR1 was chemoresponse. This reference model poten- overexpressed in brain cancer [84]. TFR1 me- tially allowed identification of new prognostic diated ROS formation and iron accumulation, markers and development of novel therapies as a crucial downstream effector of corre- [87]. Hence, TFR1 may dominantly mediate the sponding transcription factors facilitating pro- biological behaviors of brain cancer, accurately liferation of glioma and glioma-induced death predict the prognosis of GBM, and help identify of neurons [85]. Weston et al. reported that new drug targets. iron was necessary for cell division and cancer pathophysiology was affected by dysregulation Transferrin receptor 1 in breast cancer of IRPs. Based on the public data from The Cancer Genome Atlas (TCGA), they studied the Breast cancer is the most devastating type relationships between the expressions of 61 among females of Western countries and also genes coding iron regulatory proteins (IRPs) in has the highest incidence in women patients patients with Grade II-III gliomas according to of China [74]. The growth of breast cancer ce- the criteria of World Health Organization and lls requires increasing iron uptake that can be survival. The outcomes were poorer in patients realized by TFR1 over expression [76]. TFR1 with higher TRF1 expressions, indicating TFR1 has been reported to be overexpressed in

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Figure 3. TFR1 expression in various normal tissues and tumor tissues. Immunohistochemistry analysis of TFR1 in various normal tissues and tumor tissues was obtained from The Human Protein Atlas data- base. TFR1 is overexpression in multiple tumor tis- sues compared to normal tissues.

human breast cancer [88, 89], also as a suit- mammary epithelial MCF-12A cells. Moreover, able biomarker for diagnosing and treating can- TFRC antisense oligonucleotides decreased cer patients at the early stage [89]. Based on intracellular total iron and TFRC mRNA levels, public microarray datasets consisting of 674 as well as suppressed 4T1 cell proliferation in cases of breast cancer, Miller et al. detected culture medium and tumor growth and pulmo- the expression of TFR1 gene linked to breast nary metastasis in a 4T1 mouse model of mam- cancer prognosis, and high expression of TFR1 mary adenocarcinoma [91]. Wang et al. found indicated poor prognosis [90]. Singh et al. that upon breast cancer, IRP2 dominated in found that TFR1 expressions in benign and nor- iron accumulation. IRP2 overexpression was mal lesions were significantly lower than tho- related with increase of TFR1 and reduction of se in invasive carcinoma and premalignant heavy chain. Knock-down of IRP2 in lesions. In the meantime, more TFR1 was human triple-negative breast cancer cells MDA- expressed in high-grade breast cancer than in MB-231 elevated the expression of ferritin other grades [83]. Jiang et al. explored whether heavy chain and reduced that of TFR1, thereby breast cancer cells altered the expression of decreasing the labile iron pool and inhibiting TFRC. The growth of breast cancer was sup- the growth of MDA-MB-231 cells in the mam- pressed by regulating the expression of iron mary fat pad of mice [92]. Estrogen receptor transporter genes. Reverse transcription-poly- (ER)+/progesterone receptor (PR)+ invasive duc- merase chain reaction showed that more TFRC tal breast cancer accounts for approximately was expressed in MCF-7 cells than in human 45% of invasive cases in the United States of

920 Am J Cancer Res 2018;8(6):916-931 The review of TFR1 in cancer

America. Buas et al. selected 121 cases and further studies. Okazaki et al. found that the cir- 121 matching controls 12.5 months prior to cadian organization of molecular clock affected diagnosis, and divided them equally into test- TFR1 expression in colon cancer cells of mice ing and training sets. They employed a custom- and the 24 h rhythm of TFR1 expression may ized array targeting over 2000 pro- participate in cancer therapies targeting TFR1 teins, and found that TFR1 expressions were [59, 96]. The progression of colorectal cancer significantly different (P < 0.05) between cases has been related to high intake of dietary iron and matching controls. Additionally, they veri- and chronic intestinal inflammation. Chua, et fied TFR1 as a feasible plasma protein biomark- al. found high expression of TFR1 activated the er for ER+/PR+ ductal breast cancer with pre- IL-6/IL-11-Stat3 signaling pathway in the colon, diagnostic biospecimens [35]. Marques et al. enhanced DSS-induced proliferation and apo- detected TFR1 changes in tumor microenviron- ptosis of colon epithelial cells, and aggravat- ment-derived stromal inflammatory cells. TFR1 ed mucosal damage and tumorigenesis [97]. expressions in tissues of primary breast cancer Okazaki et al. observed a 24 h rhythm of IRP2 and axillary lymph nodes were measured by expression in colon-26 tumor-bearing mice, immunohistochemical assay to clarify the iron and IRP2 post-transcriptionally modulated the profiles of lymphocytes, epithelial cells and 24 h rhythm of TFR1 mRNA expression through macrophages. Macrophages and lymphocytes binding iron-response elements, i.e. RNA stem- infiltrated primary tumors, and TFR1 expres- loop structures. Moreover, the expression of sion increased in metastatic lymph nodes, be- CLOCK (Delta19) attenuated the proliferation ing related to the clinical and pathological rate of wild-type colon-26 cancer and the time- markers for poor prognosis (e.g. tumor size dependent changes of iron levels in cells. Ac- and negative hormone receptor status) [93]. cordingly, circadian organization regulated iron Rychtarcikova et al. investigated the deregu- metabolism to facilitate tumor cell proliferation lation of TFR1 in breast tumor-initiating cells [59]. Referring to TCGA database, the expres- (TICs), managing to find critical genes and pro- sions of IRP2 and TFR1 were evaluated and teins related with iron metabolism, which may compared to common mutations in cancers. be applicable to cancer diagnosis or therapy Compared with the normal colon mucosa, IRP2 [76]. TFR1 has high expressions in tumor cells, had overexpression in colorectal cancer, also upon iron deficiency in particular. Jian et al. being positively correlated with the expression studied the signaling role of TFR1 in cells of of TFR1 [77]. These results provide a thera- breast cancer by using gambogic acid (GA) and peutic target for intervening with colorectal a known of TFR1, TF. The sensitivity of tumorigenesis. TFR1 Tyr (20) phosphomutants to apoptosis mediated by GA was higher. Thus, TFR1 was a Transferrin receptor 1 in liver cancer signaling molecule indeed, and Tyr (20) phos- phorylation by Src resisted apoptosis and The liver is the most important organ related to boosted the survival of breast cancer cells [94]. iron storage [32]. Thus, liver cancer is closely Collectively, TFR1 is both a significant indepen- linked to iron metabolism and expression of dent prognostic marker and a promising thera- TFR1. Iron metabolism is altered upon hepato- peutic target for breast carcinoma. cellular carcinoma (HCC), which is typified by iron-deficient phenotype and essential to tu- Transferrin receptor 1 in colon cancer mor growth. Iron has been suggested as a risk factor mainly in HCC patients with cirrhosis and As a prevalent disease, colon cancer has the hereditary haemochromatosis (HH). Beckman eighth highest mortality rate among all cancers et al. found HFE (wild-type HH) protein compl- of adult males at present [95]. The TFR1 levels exes of TFR. Cys282Tyr and His63Asp, two HFE on cell surface, which modulate the uptake of mutations, augmented the affinity of TFR to TF, TF binding iron, are associated with cell prolif- thus promoting cellular iron uptake and HCC eration rate [96]. Since cancer cells have high- progression [98]. Holmstrom et al. detected er TFR1 expression than normal cells, it is a significantly higher mRNA levels of genes par- potential target for treating cancers. Overex- ticipating in uptake of iron, especially TFR1, in pressed in many types of cancers, TFR1 still HCC. Variations in the expressions of TFR1 in exerts unclear effects on colon cancer, needing HCCs inferred that bioavailable iron was in-

921 Am J Cancer Res 2018;8(6):916-931 The review of TFR1 in cancer creasingly required and the iron turnover was sion and body-iron stores on prostate cancer high in neoplastic cells [99]. Miwa et al. found are still controversial. By using enzymatic im- that TFRC expression was elevated with in- munoassay, Kuvibidila et al. detected serum creasing cancer stage, and its selective expres- ferritin and serum transferrin receptor (sTFR) sion in lesions undergoing proliferation indicat- levels in 72 controls and 27 males with newly ed that variations in iron homeostasis were diagnosed, untreated prostate cancer. The lev- involved in the promotion or progression of els of sTFR in males with prostate cancer sig- tumor [100]. By using immunohistochemical nificantly exceeded those without. However, assay, Sakurai et al. detected the expressions these changes of sTFR did not correlate with of TFR1 and TFR2 in tumor and paracancerous tissue inflammation, tumor stage, or acute- normal liver tissues collected from 41 patients phase proteins [103]. While Johnson et al. with HCC. They also analyzed iron uptake by detected TFR1 expressions in prostate cancer HCC cells and hepatocytes with iron staining. and normal cells, and reported that the former HCC samples had significantly higher TFR1 cells had significantly increased mRNA and pro- expressions than those of normal samples, and tein expressions of TFR1 [104]. Taken together, such expression was significantly related with altered TFR1 expression whether can be a the concentrations of serum des-gamma car- novel biomarker for accurate diagnosis of pros- boxy prothrombin and alpha-fetoprotein [101]. tate cancer and prognosis need further study. The above results revealed that TFR was expressed responding to iron deficiency in the Transferrin receptor 1 in lung cancer midst of liver carcinogenesis. Moreover, accord- ing to TCGA database, Iryna et al. found that TFR1 predominantly mediates the proliferation TFRC was overexpressed but microRNA-152 of lung cancer by regulating the uptake of iron (miR-152) level plummeted in human HCC tis- binding TF. Wang et al. demonstrated that TFR1 sue compared to those in normal liver tissue, promoters contained sequences that mediated suggesting that raised TFRC levels in human the transcriptional inhibition depending on cell HCC cells and tissues may partly be ascribed to density. TFR1 expression was affected by lung the post-transcriptional mechanism that was cancer cell density [105]. Zhu et al. reported mediated through miR-152 down-regulation. In that human lung cells SPC-A1 in which more short, targeting of TFRC specific to miR-152 TFR1 was expressed were more sensitive at may be a selective HCC therapy [78]. identical GA concentrations, and TFR1 expres- sion level in tumor tissue, which was quantified Transferrin receptor 1 in ovarian cancer by histopathological assay, may predict the sensitivity of lung cancer to treatment with GA Ovarian cancer is the fifth most fatal malignan- [106]. cy among females in the USA, and also the most deadly gynecologic type. It is well-docu- Kukulj et al. reported that TFR1 expression in mented that TFR1 played key roles in ovarian lung tumor tissue significantly surpassed that cancer. Basuli et al. demonstrated that iron in normal lung tissue. The expression in tumor metabolism underwent targetable alterations tissue was positively correlated with alpha- during ovarian cancer. As an iron importer, globulin level [107]. In addition, epidermal TFR1 expressions increased in tumor tissues growth factor receptor (EGFR), which drives collected from patients with high-grade serous oncogenesis, binds and modulates subcellular ovarian cancer. Moreover, the expression of TFR1 distribution through tyrosine kinase activ- TFR1 increased in a TIC model of ovarian ity, thereby being demanded for the import of cancer [102]. The findings can be exploited cellular iron. Accordingly, EGFR can modulate therapeutically. iron homeostasis in cells by redistributing TFR1, so it is necessary for the onset and pro- Transferrin receptor 1 in prostate cancer gression of lung cancer [79].

As a devastating health problem, prostate can- Transferrin receptor 1 in leukemia cer accounts for 25% of all newly diagnosed cancer cases and approximately 9% of all can- Human leukemias are liquid malignancies char- cer-related deaths of adult men in the USA acterized by diffuse infiltration of the bone mar- annually [74]. However, effects of TFR1 expres- row by transformed hematopoietic progenitors

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Figure 4. TFR1 and its regulatory effects on tumors Iron concentration changes significantly in cancer cells. TFR1 binds mutated HFE to promote iron intake. Iron concentration influences TFRC post-transcription by regulating the binding of IRP1 and IRP2. Meanwhile, iron concentration affects the activities of c-Jun, cyclin D and C-myc. Some miRNAs also influence TFRC transcription. These bioprocesses contribute to cell progression and tumor growth.

[108]. Iron as the most important hematopoi- carcinogenesis are complicated and often in- etic element plays a key role in leukemia. TFR1 terrelated. (Figures 4 and 5) The high expres- was initially found as an important iron uptake sion of TFR1 in tumor cells is mainly to meet the receptor inducing the growth of leukemia cell iron requirement of tumor cell proliferation [93, lines, HL-60 and KG-1 [109]. Many studies have 102]. It was reported that TFR1 is a signaling found that TFR1 was upregulated in leukemia molecule and tyrosine phosphorylation at posi- [110]. Liu et al. investigated the TFR1 could be tion 20 by Src enhances anti-apoptosis and a potential marker in the diagnosis of acute potentiates breast cancer cell survival [94]. leukemia (AL) [111]. Płoszyńska A et al. evalu- TFR1 was also reported as a mitochondrial reg- ated TFR1 expression on acute lymphoblastic ulator contributed to cancer cell growth via ac- leukemia (ALL) cells. TFR1 expression was sta- tivating JNK signaling pathway [36]. Jeong et tistically higher on T-lineage leukemias while in al. reported that TFR1 induced the growth the B lineage ALL, a significant difference in of human pancreatic ductal adenocarcinoma TFR1 expression existed between precursor B (PDAC) by supporting ROS production and ALL and mature B-ALL, which showed higher mitochondrial respiration in tumor cells. Up- TFR1 expression. TFR1 expression positively regulation of TFR1 expression generated ROS correlated with Hgb concentration at diagnosis in PDAC cells by inducing oxidative phosphory- [112]. In summary, TFR1 could be a good target lation. Moreover, PDAC growth required ROS for leukemia therapy. derived from mitochondria. Furthermore, the Mechanisms by which transferrin receptor 1 sensitivity of PDAC cells to oxidative stress affects cancers was determined by TFR1 expression. By trigger- ing ROS production and mitochondrial respira- Given that TFR1 is widely overexpressed in can- tion, TFR1 significantly participated in pancre- cers, the regulatory mechanisms of TFR1 for atic cancer growth and survival [34]. Wang et

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phosphatase and p21/cdk- n1a, and activation of Akt and mitogen-activated protein kin- ase. When the cell cycle regu- lators were inactivated, cells were prone to entry into the S phase. TFR not only affected proliferation, but also facilitat- ed release of glutamate, caus- ing decrease in neuron mass through the mediation by N- methyl-D-aspartate-receptor [85]. O’Donnell et al. proved that TFR1 was a key down- stream target for c-Myc, and the expressions of TFR1 in both in vitro and in vivo models of B-cell lymphoma were acti- vated by c-Myc which bound the conserved region of TFR1 directly. Also, inhibiting TFR1 attenuated cell proliferation and induced arrest in the G1 phase without influencing the size of cells. Consistently, ex- Figure 5. TFR1 interaction network. Based on the search tool of the Euro- pression profiling showed that pean Molecular Biology Laboratory for retrieving interacting genes/proteins, depletion of TFR1 changed the an interaction network with confidence levels of > 0.7 is exhibited for geneti- expressions of cell cycle-regu- cally interacting, possibly TFR1-related proteins. A thicker line represents a stronger interaction. latory genes. Additionally, in- creasing TFR1 expression was beneficial to cell growth and al. found that IRP2 increased TFR1, playing a significantly boosted in vivo tumor formation key role in breast cancer progression. As an mediated by c-Myc. The results mentioned early nodal point for iron metabolism changes above provide molecular bases for elevated upon breast cancer, dysregulation of IRP2 may expressions of TFR1 in human tumors, con- result in unsatisfactory outcomes of some firming the effects of TFR1 on the network of patients [92]. Pham et al. found that sphingo- c-Myc target genes. Targeting TFR1 may be sine kinase 1, a lipid kinase catalyzing the useful for cancer therapy [115]. production of sphingosine 1-phosphate, could modulate cell proliferation, survival as well as Therapeutic potential of targeting TFR1 in neoplastic transformation by promoting TFR1 cancers expression [113]. Bayeva et al. reported that iron homeostasis was modulated by mammali- As TFR1 is expressed in many kinds of cancers an target of rapamycin (mTOR) through varia- and significantly involved in tumorigenesis and tions of cellular iron flux and regulation of TFR1 progression of cancers, it may be feasible to stability. They identified an anti-inflammatory intervene with the progression of cancers by protein, tristetraprolin, as the downstream tar- targeting TFR1. As evidenced by currently av- get of mTOR which bound TFR1 mRNA and fa- ailable studies targeting TFR1, curcumin was cilitated its degradation. Therefore, TFR1 in- among the most successful chemopreventive duced carcinogenesis by regulating metabo- compounds. Jiao et al. evaluated the influence lism, inflammation and iron [114]. Chirasani et of curcumin on iron regulatory proteins and al. demonstrated that TFR1-induced accumu- TFR1. Both TFR1 and IRP increased responding lation of oxidants altered cellular signaling to curcumin [116]. Yang et al. also found cur- through inactivation of pRB protein tyrosine cumin induced the autophagy and apoptosis

924 Am J Cancer Res 2018;8(6):916-931 The review of TFR1 in cancer

Figure 6. Future directions for TFR1 research in tumor. The direct effects of TFR1 expression on carcinogenesis remains further study. TFR1’s functions and mechanisms in cancer cell ferroptosis are still unclear. Nanomedicine combine with magnetic fields targeting TFR1 will be a potential cancer therapy. of different tumor cells by inhibiting TFR1 ex- could interfere with binding between TFR1 and pression, inferring that curcumin was a poten- TF, inhibited the iron intake of adult T-cell leuke- tial TFR1 inhibitor for cancer therapy [117]. mia/lymphoma, which may become a promis- Anti-transferrin receptor monoclonal antibody ing therapy for the treatment of adult T-cell leu- A24 significantly blocks the proliferation of kemia/lymphoma [123]. T-cell leukemia cell, induces apoptosis of tumor T lymphocytes from acute T-cell leukemia pa- Conclusions and future directions tients [118, 119]. Also, miRNA drug targeting TFR1 has been reported to be a good drug in We herein reviewed the roles of TFR1 in the clinical treatment of leukemia [120]. Moreover, onset and progression of cancers, its regulato- nanomedicine and antibodies targeting TFR1 ry effects on tumorigenesis, together with the have been developed for tumor-specific target- potential of TFR1-targeted cancer therapies. ed therapy, providing a valuable opportunity for Regardless of considerable studies concern- developing eligible TFR1 inhibitors in the field ing TFR1 since it was discovered, several key of precision oncology [121, 122]. TFR1 is high- issues still exist. (Figure 6) Firstly, whether ly expressed in adult T-cell leukemia/lympho- TFR1 interacts with additional signaling path- ma. Shimosaki et al. developed a novel mole- ways or proteins on the cellular level remains cular-targeted therapy against TFR1 to modu- elusive, which may be essential to the develop- late HTLV-1-associated adult T-cell leukemia/ ment of therapies based on TFR1. Being dif- lymphoma iron metabolism to inhibit the adult ferent from the traditional apoptosis and ne- T-cell leukemia/lymphoma. JST-TFR09, an anti- crosis, the recently discovered ferroptosis is body to human TFR1, has great affinity to TF- caused by iron-dependent accumulation of lipid R1 on adult T-cell leukemia/lymphoma cells. It peroxides. Cells which are subjected to ferrop-

925 Am J Cancer Res 2018;8(6):916-931 The review of TFR1 in cancer totic death suffer from shrinkage of volumes [3] Drakesmith H, Nemeth E, Ganz T. Ironing out and raised density of the mitochondrial mem- ferroportin. Cell Metab 2015; 22: 777-787. brane. Iron metabolism plays a curial role in fer- [4] Bang S, Lee YM, Hong S, Cho KB, Nishida Y, roptosis [124]. Ferroptosis induced by erastin Seo MS, Sarangi R, Fukuzumi S, Nam W. Re- dox-inactive metal ions modulate the reactivity or Cys2 deprivation is prevented by silencing and oxygen release of mononuclear non-haem TFRC gene, which encodes TFR1 required for iron(III)-peroxo complexes. Nat Chem 2014; 6: the uptake of TF-iron complexes into cells. 934-940. However, TFR1, an important iron intake recep- [5] Ward RJ, Zucca FA, Duyn JH, Crichton RR, Zec- tor in cancer cells, still has unclear functions ca L. The role of iron in brain ageing and neuro- and mechanisms in ferroptosis. Furthermore, degenerative disorders. Lancet Neurol 2014; TFR1 expressions are up-regulated in some 13: 1045-1060. drug-resistant human cancer cells [45], requir- [6] Čorić I, Mercado BQ, Bill E, Vinyard DJ, Holland PL. Binding of dinitrogen to an iron-sulfur-car- ing more in-depth studies though. Last but not bon site. Nature 2015; 526: 96-99. least, since drug therapies may suppress TFR1 [7] Adak L, Kawamura S, Toma G, Takenaka T, Iso- expression, developing a TFR1-specific revers- zaki K, Takaya H, Orita A, Li HC, TKM S, Naka- ible antagonist is the only single most effective mura M. Synthesis of aryl c-glycosides via iron- strategy for both basic research and clinical catalyzed cross coupling of halosugars: practice. Notably, tumor progression can be stereoselective anomeric arylation of glycosyl inhibited through magnetic fields that aug- radicals. J Am Chem Soc 2017; 139: 10693- ment the concentrations of TFR1-targeted su- 10701. [8] Schlesier J, Rohde M, Gerhardt S, Einsle O. A perparamagnetic iron oxides in tumor tissues, conformational switch triggers nitrogenase inspiring future cancer therapy [125-127]. protection from oxygen damage by shethna protein iI (FeSII). J Am Chem Soc 2016; 138: Acknowledgements 239-247. [9] Ghosh C, Seal M, Mukherjee S, Ghosh DS. Al- We gratefully acknowledge the funding from zheimer’s disease: a heme-aβ perspective. Acc the Science and Technology Planning Project Chem Res 2015; 48: 2556-2564. of Shenzhen of China (JCYJ2017041214090- [10] Barañano DE, Snyder SH. Neural roles for 4406), and the National Basic Research Pro- heme oxygenase: contrasts to nitric oxide syn- gram of China (51777171). thase. Proc Natl Acad Sci U S A 2001; 98: 10996-11002. Disclosure of conflict of interest [11] Paul A, Drecourt A, Petit F, Deguine DD, Vasni- er C, Oufadem M, Masson C, Bonnet C, Mas- None. moudi S, Mosnier I, Mahieu L, Bouccara D, Kaplan J, Challe G, Domange C, Mochel F, Address correspondence to: Peng Shang, Research Sterkers O, Gerber S, Nitschke P, Bole-Feysot & Development Institute in Shenzhen, Northwestern C, Jonard L, Gherbi S, Mercati O, Ben AI, Lyon- net S, Rötig A, Delahodde A, Marlin S. FDXR Polytechnical University, Shenzhen 518057, China; mutations cause sensorial neuropathies and Key Laboratory for Space Bioscience and Biote- expand the spectrum of mitochondrial fe-s- chnology, Institute of Special Environment Bio- synthesis diseases. Am J Hum Genet 2017; physics, School of Life Science, Northwestern 101: 630-637. Polytechnical University, Xi’an 710072, Shaanxi, [12] Drakesmith H, Prentice A. Viral infection and China. E-mail: [email protected] iron metabolism. Nat Rev Microbiol 2008; 6: 541-552. References [13] Liu X, Theil EC. : dynamic manage- ment of biological iron and oxygen chemistry. [1] Xue X, Ramakrishnan SK, Weisz K, Triner D, Xie Acc Chem Res 2005; 38: 167-175. L, Attili D, Pant A, Győrffy B, Zhan M, Carter-Su [14] Cheng Q, Zhang X, Jiang J, Zhao G, Wang Y, Xu C, Hardiman KM, Wang TD, Dame MK, Varani Y, Xu X, Ma H. Postmenopausal iron overload J, Brenner D, Fearon ER, Shah YM. Iron uptake exacerbated bone loss by promoting the degra- via DMT1 integrates cell cycle with JAK-STAT3 dation of type i collagen. Biomed Res Int 2017; signaling to promote colorectal tumorigenesis. 2017: 1345193. Cell Metab 2016; 24: 447-461. [15] Zhu C, Yang F, Fan D, Wang Y, Yu Y. Higher iron [2] Torti SV, Torti FM. Iron and cancer: more ore to bioavailability of a human-like collagen iron be mined. Nat Rev Cancer 2013; 13: 342-355. complex. J Biomater Appl 2017; 32: 82-92.

926 Am J Cancer Res 2018;8(6):916-931 The review of TFR1 in cancer

[16] Tchetina EV, Markova GA, Poole AR, Zukor DJ, [26] Fearnhead HO, Vandenabeele P, Vanden BT. Antoniou J, Makarov SA, Kuzin AN. Deferox- How do we fit ferroptosis in the family of regu- amine suppresses collagen cleavage and pro- lated cell death. Cell Death Differ 2017; 24: tease, cytokine, and col10a1 expression and 1991-1998. upregulates ampk and krebs cycle genes in [27] Mai TT, Hamaï A, Hienzsch A, Cañeque T, Mül- human osteoarthritic cartilage. Int J Rheuma- ler S, Wicinski J, Cabaud O, Leroy C, David A, tol 2016; 2016: 6432867. Acevedo V, Ryo A, Ginestier C, Birnbaum D, [17] Milto IV, Suhodolo IV, Prokopieva VD, Kliment- Charafe-Jauffret E, Codogno P, Mehrpour M, eva TK. Molecular and cellular bases of iron Rodriguez R. Salinomycin kills cancer stem metabolism in humans. Biochemistry (Mosc) cells by sequestering iron in lysosomes. Nat 2016; 81: 549-564. Chem 2017; 9: 1025-1033. [18] Stockwell BR, Friedmann Angeli JP, Bayir H, [28] Hamaï A, Cañeque T, Müller S, Mai TT, Hien- Bush AI, Conrad M, Dixon SJ, Fulda S, Gascón zsch A, Ginestier C, Charafe-Jauffret E, Codog- S, Hatzios SK, Kagan VE, Noel K, Jiang X, Link- no P, Mehrpour M, Rodriguez R. An iron hand ermann A, Murphy ME, Overholtzer M, Oyagi A, over cancer stem cells. Autophagy 2017; 13: Pagnussat GC, Park J, Ran Q, Rosenfeld CS, 1465-1466. Salnikow K, Tang D, Torti FM, Torti SV, Toyokuni [29] Zanganeh S, Hutter G, Spitler R, Lenkov O, S, Woerpel KA, Zhang DD. Ferroptosis: a regu- Mahmoudi M, Shaw A, Pajarinen JS, Nejadnik lated cell death nexus linking metabolism, re- H, Goodman S, Moseley M, Coussens LM, Dal- dox biology, and disease. Cell 2017; 171: 273- drup-Link HE. Iron oxide nanoparticles inhibit 285. tumour growth by inducing pro-inflammatory [19] Tarangelo A, Dixon SJ. Nanomedicine: an iron macrophage polarization in tumour tissues. age for cancer therapy. Nat Nanotechnol 2016; Nat Nanotechnol 2016; 11: 986-994. 11: 921-922. [30] Kim SE, Zhang L, Ma K, Riegman M, Chen F, [20] Wang YF, Zhang J, Su Y, Shen YY, Jiang DX, Hou Ingold I, Conrad M, Turker MZ, Gao M, Jiang X, YY, Geng MY, Ding J, Chen Y. G9a regulates Monette S, Pauliah M, Gonen M, Zanzonico P, breast cancer growth by modulating iron ho- Quinn T, Wiesner U, Bradbury MS, Overholtzer meostasis through the repression of ferroxi- M. Ultrasmall nanoparticles induce ferroptosis in nutrient-deprived cancer cells and suppress dase . Nat Commun 2017; 8: 274. tumour growth. Nat Nanotechnol 2016; 11: [21] Kerins MJ, Ooi A. The roles of NRF2 in modulat- 977-985. ing cellular iron homeostasis. Antioxid Redox [31] Szemraj M, Oszajca K, Szemraj J, Jurowski P. Signal 2017; [Epub ahead of print]. MicroRNA expression analysis in serum of pa- [22] Luscieti S, Galy B, Gutierrez L, Reinke M, Cou- tients with congenital hemochromatosis and so J, Shvartsman M, Di PA, Witke W, Hentze age-related macular degeneration (AMD). Med MW, Pilo BP, Sanchez M. The actin binding pro- Sci Monit 2017; 23: 4050-4060. tein profilin 2 is a novel regulator of ironho- [32] Crielaard BJ, Lammers T, Rivella S. Targeting meostasis. Blood 2017; 30: 1934-1945. iron metabolism in drug discovery and deliv- [23] Schoenfeld JD, Sibenaller ZA, Mapuskar KA, ery. Nat Rev Drug Discov 2017; 16: 400-423. Wagner BA, Cramer-Morales KL, Furqan M, [33] Aisen P. Transferrin receptor 1. Int J Biochem Sandhu S, Carlisle TL, Smith MC, Abu HT, Berg Cell Biol 2004; 36: 2137-2143. DJ, Zhang J, Keech J, Parekh KR, Bhatia S, [34] Jeong SM, Hwang S, Seong RH. Transferrin re- Monga V, Bodeker KL, Ahmann L, Vollstedt S, ceptor regulates pancreatic cancer growth by Brown H, Shanahan Kauffman EP, Schall ME, modulating mitochondrial respiration and ROS Hohl RJ, Clamon GH, Greenlee JD, Howard MA, generation. Biochem Biophys Res Commun Schultz MK, Smith BJ, Riley DP, Domann FE, 2016; 471: 373-379. Cullen JJ, Buettner GR, Buatti JM, Spitz DR, Al- [35] Buas MF, Rho JH, Chai X, Zhang Y, Lampe PD, len BG. O2(-) and H2O2-mediated disruption of Li CI. Candidate early detection protein bio- fe metabolism causes the differential suscep- markers for ER+/PR+ invasive ductal breast tibility of nsclc and gbm cancer cells to phar- carcinoma identified using pre-clinical plasma macological ascorbate. Cancer Cell 2017; 31: from the WHI observational study. Breast Can- 487-500, e8. cer Res Treat 2015; 153: 445-454. [24] Jung M, Weigert A, Mertens C, Rehwald C, [36] Senyilmaz D, Virtue S, Xu X, Tan CY, Griffin JL, Brüne B. Iron handling in tumor-associated Miller AK, Vidal-Puig A, Teleman AA. Regulation macrophages-is there a new role for lipocal- of mitochondrial morphology and function by in-2. Front Immunol 2017; 8: 1171. stearoylation of TFR1. Nature 2015; 525: 124- [25] Latunde-Dada GO. Ferroptosis: role of lipid per- 128. oxidation, iron and ferritinophagy. Biochim Bio- [37] Moreno-Navarrete JM, Novelle MG, Catalán V, phys Acta 2017; 1861: 1893-1900. Ortega F, Moreno M, Gomez-Ambrosi J, Xifra G,

927 Am J Cancer Res 2018;8(6):916-931 The review of TFR1 in cancer

Serrano M, Guerra E, Ricart W, Frühbeck G, hematopoietic stem cells. Nat Commun 2017; Diéguez C, Fernández-Real JM. Insulin resis- 8: 16114. tance modulates iron-related proteins in adi- [51] Anderson SA, Nizzi CP, Chang YI, Deck KM, pose tissue. Diabetes Care 2014; 37: 1092- Schmidt PJ, Galy B, Damnernsawad A, Broman 1100. AT, Kendziorski C, Hentze MW, Fleming MD, [38] Daniels TR, Bernabeu E, Rodríguez JA, Patel S, Zhang J, Eisenstein RS. The IRP1-HIF-2α axis Kozman M, Chiappetta DA, Holler E, Ljubimova coordinates iron and oxygen sensing with JY, Helguera G, Penichet ML. The transferrin erythropoiesis and iron absorption. Cell Metab receptor and the targeted delivery of therapeu- 2013; 17: 282-290. tic agents against cancer. Biochim Biophys [52] Ghosh MC, Zhang DL, Jeong SY, Kovtunovych Acta 2012; 1820: 291-317. G, Ollivierre-Wilson H, Noguchi A, Tu T, Senecal [39] Nagai K, Nakahata S, Shimosaki S, Tamura T, T, Robinson G, Crooks DR, Tong WH, Ramas- Kondo Y, Baba T, Taki T, Taniwaki M, Kurosawa wamy K, Singh A, Graham BB, Tuder RM, Yu ZX, G, Sudo Y, Okada S, Sakoda S, Morishita K. De- Eckhaus M, Lee J, Springer DA, Rouault TA. De- velopment of a complete human anti-human letion of iron regulatory protein 1 causes poly- transferrin receptor C antibody as a novel cythemia and pulmonary hypertension in mice marker of oral dysplasia and oral cancer. Can- through translational derepression of HIF2α. cer Med 2014; 3: 1085-1099. Cell Metab 2013; 17: 271-281. [40] Lopez A, Cacoub P, Macdougall IC, Peyrin-Bi- [53] Udensi UK, Tackett AJ, Byrum S, Avaritt NL, roulet L. Iron deficiency anaemia. Lancet 2016; Sengupta D, Moreland LW, Tchounwou PB, 387: 907-916. Isokpehi RD. Proteomics-based identification [41] Widera A, Norouziyan F, Shen WC. Mecha- of differentially abundant proteins from human nisms of TfR-mediated transcytosis and sort- keratinocytes exposed to arsenic trioxide. J ing in epithelial cells and applications toward Proteomics Bioinform 2014; 7: 166-178. drug delivery. Adv Drug Deliv Rev 2003; 55: [54] Kawabata H. Progress in iron metabolism re- search. Rinsho Ketsueki 2017; 58: 1864- 1439-1466. 1871. [42] Kaplan J. Mechanisms of cellular iron acquisi- [55] Barisani D, Conte D. Transferrin receptor 1 tion: another iron in the fire. Cell 2002; 111: (TfR1) and putative stimulator of Fe transport 603-606. (SFT) expression in iron deficiency and over- [43] Nai A, Lidonnici MR, Rausa M, Mandelli G, Pa- load: an overview. Blood Cells Mol Dis 2002; gani A, Silvestri L, Ferrari G, Camaschella C. 29: 498-505. The second transferrin receptor regulates red [56] Roodman GD. Osteoclasts pump iron. Cell blood cell production in mice. Blood 2015; Metab 2009; 9: 405-406. 125: 1170-1179. [57] Otero GA, Pliego-Rivero FB, Contreras G, Ricar- [44] Trinder D, Baker E. : a do J, Fernández T. Iron supplementation brings new molecule in iron metabolism. Int J Bio- up a lacking P300 in iron deficient children. chem Cell Biol 2003; 35: 292-296. Clin Neurophysiol 2004; 115: 2259-2266. [45] Kazan HH, Urfali-Mamatoglu C, Gunduz U. Iron [58] Wei H, Ke HL, Lin J, Shete S, Wood CG, Hildeb- metabolism and drug resistance in cancer. randt MA. MicroRNA target site polymorphisms Biometals 2017; 30: 629-641. in the VHL-HIF1α pathway predict renal cell [46] Rienzo M, Schiano C, Casamassimi A, Grimaldi carcinoma risk. Mol Carcinog 2014; 53: 1-7. V, Infante T, Napoli C. Identification of valid ref- [59] Okazaki F, Matsunaga N, Okazaki H, Azuma H, erence housekeeping genes for gene expres- Hamamura K, Tsuruta A, Tsurudome Y, Ogino T, sion analysis in tumor neovascularization stud- Hara Y, Suzuki T, Hyodo K, Ishihara H, Kikuchi ies. Clin Transl Oncol 2013; 15: 211-218. H, To H, Aramaki H, Koyanagi S, Ohdo S. Circa- [47] Gammella E, Buratti P, Cairo G, Recalcati S. dian clock in a mouse colon tumor regulates The transferrin receptor: the cellular iron gate. intracellular iron levels to promote tumor pro- Metallomics 2017; 9: 1367-1375. gression. J Biol Chem 2016; 291: 7017-7028. [48] Ganz T. Iron homeostasis: fitting the puzzle [60] Marziali G, Perrotti E, Ilari R, Lulli V, Coccia EM, pieces together. Cell Metab 2008; 7: 288-290. Moret R, Kühn LC, Testa U, Battistini A. Role of [49] Lazaros G, Antonatou K, Vassilopoulos D. The Ets-1 in transcriptional regulation of transfer- therapeutic role of interleukin-1 inhibition in rin receptor and erythroid differentiation. On- idiopathic recurrent pericarditis: current evi- cogene 2002; 21: 7933-7944. dence and future challenges. Front Med (Laus- [61] Lok CN, Ponka P. Identification of a hypoxia re- anne) 2017; 4: 78. sponse element in the transferrin receptor [50] Muto Y, Nishiyama M, Nita A, Moroishi T, Na- gene. J Biol Chem 1999; 274: 24147-24152. kayama KI. Essential role of FBXL5-mediated [62] Biswas S, Tapryal N, Mukherjee R, Kumar R, cellular iron homeostasis in maintenance of Mukhopadhyay CK. Insulin promotes iron up-

928 Am J Cancer Res 2018;8(6):916-931 The review of TFR1 in cancer

take in human hepatic cell by regulating trans- therapy-resistant breast cancer stem cells via ferrin receptor-1 transcription mediated by hy- regulation of mitochondrial oxidative phos- poxia inducible factor-1. Biochim Biophys Acta phorylation. Cell Metab 2017; 26: 633-647.e7. 2013; 1832: 293-301. [74] Liu Z, Wu H, Wei Z, Wang X, Shen P, Wang S, [63] Lok CN, Ponka P. Identification of an erythroid Wang A, Chen W, Lu Y. TRPM8: a potential tar- active element in the transferrin receptor get for cancer treatment. J Cancer Res Clin On- gene. J Biol Chem 2000; 275: 24185-24190. col 2016; 142: 1871-1881. [64] 1q21.3 amplification is linked to [75] Augustin HG, Koh GY. Organotypic vasculature: breast cancer recurrence. Cancer Discov 2017. From descriptive heterogeneity to functional [65] Reddy A, Zhang J, Davis NS, Moffitt AB, Love pathophysiology. Science 2017; 357. CL, Waldrop A, Leppa S, Pasanen A, Meriranta [76] Rychtarcikova Z, Lettlova S, Tomkova V, Koren- L, Karjalainen-Lindsberg ML, Nørgaard P, Ped- kova V, Langerova L, Simonova E, Zjablovskaja ersen M, Gang AO, Høgdall E, Heavican TB, P, Alberich-Jorda M, Neuzil J, Truksa J. Tumor- Lone W, Iqbal J, Qin Q, Li G, Kim SY, Healy J, initiating cells of breast and prostate origin Richards KL, Fedoriw Y, Bernal-Mizrachi L, Koff show alterations in the expression of genes JL, Staton AD, Flowers CR, Paltiel O, Gold- related to iron metabolism. Oncotarget 2017; schmidt N, Calaminici M, Clear A, Gribben J, 8: 6376-6398. Nguyen E, Czader MB, Ondrejka SL, Collie A, [77] Horniblow RD, Bedford M, Hollingworth R, Ev- Hsi ED, Tse E, Au-Yeung RKH, Kwong YL, Srivas- ans S, Sutton E, Lal N, Beggs A, Iqbal TH, Tsel- tava G, Choi WWL, Evens AM, Pilichowska M, epis C. BRAF mutations are associated with Sengar M, Reddy N, Li S, Chadburn A, Gordon increased iron regulatory protein-2 expression LI, Jaffe ES, Levy S, Rempel R, Tzeng T, Happ in colorectal tumorigenesis. Cancer Sci 2017; LE, Dave T, Rajagopalan D, Datta J, Dunson 108: 1135-1143. DB, Dave SS. Genetic and functional drivers of [78] Kindrat I, Tryndyak V, de Conti A, Shpyleva S, diffuse large b cell lymphoma. Cell 2017; 171: Mudalige TK, Kobets T, Erstenyuk AM, Beland 481-494, e15. FA, Pogribny IP. MicroRNA-152-mediated dys- [66] Zanconato F, Cordenonsi M, Piccolo S. YAP/ regulation of hepatic transferrin receptor 1 in TAZ at the roots of cancer. Cancer Cell 2016; liver carcinogenesis. Oncotarget 2016; 7: 29: 783-803. 1276-1287. [67] Vernieri C, Casola S, Foiani M, Pietrantonio F, [79] Wang B, Zhang J, Song F, Tian M, Shi B, Jiang de Braud F, Longo V. Targeting cancer metabo- H, Xu W, Wang H, Zhou M, Pan X, Gu J, Yang S, lism: dietary and pharmacologic interventions. Jiang L, Li Z. EGFR regulates iron homeostasis Cancer Discov 2016; 6: 1315-1333. to promote cancer growth through redistribu- [68] Kruiswijk F, Labuschagne CF, Vousden KH. p53 tion of transferrin receptor 1. Cancer Lett in survival, death and metabolic health: a life- 2016; 381: 331-340. guard with a licence to kill. Nat Rev Mol Cell [80] Uhlén M, Fagerberg L, Hallström BM, Lindskog Biol 2015; 16: 393-405. C, Oksvold P, Mardinoglu A, Sivertsson Å, [69] Bernardi MP, Ngan SY, Michael M, Lynch AC, Kampf C, Sjöstedt E, Asplund A, Olsson I, Ed- Heriot AG, Ramsay RG, Phillips WA. Molecular lund K, Lundberg E, Navani S, Szigyarto CA, biology of anal squamous cell carcinoma: im- Odeberg J, Djureinovic D, Takanen JO, Hober S, plications for future research and clinical inter- Alm T, Edqvist PH, Berling H, Tegel H, Mulder J, vention. Lancet Oncol 2015; 16: e611-621. Rockberg J, Nilsson P, Schwenk JM, Hamsten [70] Ngambenjawong C, Gustafson HH, Pun SH. M, von FK, Forsberg M, Persson L, Johansson Progress in tumor-associated macrophage F, Zwahlen M, von HG, Nielsen J, Pontén F. Pro- (TAM)-targeted therapeutics. Adv Drug Deliv teomics. Tissue-based map of the human pro- Rev 2017; 114: 206-221. teome. Science 2015; 347: 1260419. [71] Garofalo M, Croce CM. Role of microRNAs in [81] Gu Z, Wang H, Xia J, Yang Y, Jin Z, Xu H, Shi J, maintaining cancer stem cells. Adv Drug Deliv De Domenico I, Tricot G, Zhan F. Decreased fer- Rev 2015; 81: 53-61. roportin promotes myeloma cell growth and [72] Berindan-Neagoe I, Monroig PC, Pasculli B, osteoclast differentiation. Cancer Res 2015; Calin GA. MicroRNAome genome: a treasure 75: 2211-2221. for cancer diagnosis and therapy. CA Cancer J [82] Ohkuma M, Haraguchi N, Ishii H, Mimori K, Clin 2014; 64: 311-336. Tanaka F, Kim HM, Shimomura M, Hirose H, [73] Lee KM, Giltnane JM, Balko JM, Schwarz LJ, Yanaga K, Mori M. Absence of CD71 transferrin Guerrero-Zotano AL, Hutchinson KE, Nixon MJ, receptor characterizes human gastric adeno- Estrada MV, Sánchez V, Sanders ME, Lee T, Gó- squamous carcinoma stem cells. Ann Surg On- mez H, Lluch A, Pérez-Fidalgo JA, Wolf MM, An- col 2012; 19: 1357-1364. drejeva G, Rathmell JC, Fesik SW, Arteaga CL. [83] Singh M, Mugler K, Hailoo DW, Burke S, MYC and MCL1 cooperatively promote chemo- Nemesure B, Torkko K, Shroyer KR. Differential

929 Am J Cancer Res 2018;8(6):916-931 The review of TFR1 in cancer

expression of transferrin receptor (TfR) in a potentiates breast cancer cell survival. J Biol spectrum of normal to malignant breast tis- Chem 2011; 286: 35708-35715. sues: implications for in situ and invasive carci- [95] Carvalho C, Glynne-Jones R. Challenges be- noma. Appl Immunohistochem Mol Morphol hind proving efficacy of adjuvant chemothera- 2011; 19: 417-423. py after preoperative chemoradiation for rectal [84] Rosager AM, Sørensen MD, Dahlrot RH, Han- cancer. Lancet Oncol 2017; 18: e354-e363. sen S, Schonberg DL, Rich JN, Lathia JD, Kris- [96] Okazaki F, Matsunaga N, Okazaki H, Utoguchi tensen BW. Transferrin receptor-1 and ferritin N, Suzuki R, Maruyama K, Koyanagi S, Ohdo S. heavy and chains in astrocytic brain tu- Circadian rhythm of transferrin receptor 1 mors: Expression and prognostic value. PLoS controlled by c-Myc in colon One 2017; 12: e0182954. cancer-bearing mice. Cancer Res 2010; 70: [85] Chirasani SR, Markovic DS, Synowitz M, Eichler 6238-6246. SA, Wisniewski P, Kaminska B, Otto A, Wanker [97] Chua AC, Klopcic BR, Ho DS, Fu SK, Forrest CH, E, Schäfer M, Chiarugi P, Meier JC, Ketten- Croft KD, Olynyk JK, Lawrance IC, Trinder D. Di- mann H, Glass R. Transferrin-receptor-mediat- etary iron enhances colonic inflammation and ed iron accumulation controls proliferation and IL-6/IL-11-Stat3 signaling promoting colonic glutamate release in glioma cells. J Mol Med tumor development in mice. PLoS One 2013; (Berl) 2009; 87: 153-167. 8: e78850. [86] Weston C, Klobusicky J, Weston J, Connor J, [98] Beckman LE, Hägerstrand I, Stenling R, Van Toms SA, Marko NF. Aberrations in the iron Landeghem GF, Beckman L. Interaction be- regulatory gene signature are associated with tween haemochromatosis and transferrin re- decreased survival in diffuse infiltrating glio- ceptor genes in hepatocellular carcinoma. On- mas. PLoS One 2016; 11: e0166593. cology 2000; 59: 317-322. [87] Yu X, Feng L, Liu D, Zhang L, Wu B, Jiang W, [99] Holmström P, Gåfvels M, Eriksson LC, Dzikaite Han Z, Cheng S. Quantitative proteomics re- V, Hultcrantz R, Eggertsen G, Stål P. Expression veals the novel co-expression signatures in of iron regulatory genes in a rat model of hepa- early brain development for prognosis of glio- tocellular carcinoma. Liver Int 2006; 26: 976- blastoma multiforme. Oncotarget 2016; 7: 985. 14161-14171. [100] Takahashi M, Shibutani M, Woo GH, Inoue K, [88] Pizzamiglio S, De Bortoli M, Taverna E, Signore Fujimoto H, Igarashi K, Kanno J, Hirose M, Ni- M, Veneroni S, Cho WC, Orlandi R, Verderio P, shikawa A. Cellular distributions of molecules Bongarzone I. Expression of iron-related pro- with altered expression specific to the tumor teins differentiate non-cancerous and cancer- promotion process from the early stage in a rat ous breast tumors. Int J Mol Sci 2017; 18. two-stage hepatocarcinogenesis model. Carci- [89] Habashy HO, Powe DG, Staka CM, Rakha EA, nogenesis 2008; 29: 2218-2226. Ball G, Green AR, Aleskandarany M, Paish EC, [101] Sakurai K, Sohda T, Ueda S, Tanaka T, Hirano Douglas MR, Nicholson RI, Ellis IO, Gee JM. G, Yokoyama K, Morihara D, Aanan A, Takeya- Transferrin receptor (CD71) is a marker of poor ma Y, Irie M, Iwata K, Syakado S, Noritomiz T, prognosis in breast cancer and can predict re- Yamashita Y, Sakisaka S. Immunohistochemi- sponse to tamoxifen. Breast Cancer Res Treat cal demonstration of transferrin receptor 1 2010; 119: 283-293. and 2 in human hepatocellular carcinoma tis- [90] Miller LD, Coffman LG, Chou JW, Black MA, sue. Hepatogastroenterology 2014; 61: 426- Bergh J, D’Agostino R, Torti SV, Torti FM. An 430. iron regulatory gene signature predicts out- [102] Basuli D, Tesfay L, Deng Z, Paul B, Yamamoto come in breast cancer. Cancer Res 2011; 71: Y, Ning G, Xian W, McKeon F, Lynch M, Crum 6728-6737. CP, Hegde P, Brewer M, Wang X, Miller LD, Dy- [91] Jiang XP, Elliott RL, Head JF. Manipulation of ment N, Torti FM, Torti SV. Iron addiction: a iron transporter genes results in the suppres- novel therapeutic target in ovarian cancer. On- sion of human and mouse mammary adeno- cogene 2017; 36: 4089-4099. carcinomas. Anticancer Res 2010; 30: 759- [103] Kuvibidila S, Gauthier T, Warrier RP, Rayford W. 765. Increased levels of serum transferrin receptor [92] Wang W, Deng Z, Hatcher H, Miller LD, Di X, and serum transferrin receptor/log ferritin ra- Tesfay L, Sui G, D’Agostino RB, Torti FM, Torti tios in men with prostate cancer and the impli- SV. IRP2 regulates breast tumor growth. Can- cations for body-iron stores. J Lab Clin Med cer Res 2014; 74: 497-507. 2004; 144: 176-182. [93] Marques O, Porto G, Rêma A, Faria F, Cruz PA, [104] Johnson IR, Parkinson-Lawrence EJ, Shandala Gomez-Lazaro M, Silva P, Martins da Silva B, T, Weigert R, Butler LM, Brooks DA. Altered en- Lopes C. Local iron homeostasis in the breast dosome biogenesis in prostate cancer has bio- ductal carcinoma microenvironment. BMC marker potential. Mol Cancer Res 2014; 12: Cancer 2016; 16: 187. 1851-1862. [94] Jian J, Yang Q, Huang X. Src regulates Tyr (20) [105] Wang J, Chen G, Pantopoulos K. Inhibition of phosphorylation of transferrin receptor-1 and transferrin receptor 1 transcription by a cell

930 Am J Cancer Res 2018;8(6):916-931 The review of TFR1 in cancer

density response element. Biochem J 2005; [118] Callens C, Moura IC, Lepelletier Y, Coulon S, 392: 383-388. Renand A, Dussiot M, Ghez D, Benhamou M, [106] Zhu X, Zhang H, Lin Y, Chen P, Min J, Wang Z, Monteiro RC, Bazarbachi A, Hermine O. Recent Xiao W, Chen B. Mechanisms of gambogic ac- advances in adult T-cell leukemia therapy: fo- id-induced apoptosis in non-small cell lung cus on a new anti-transferrin receptor mono- cancer cells in relation to transferrin receptors. clonal antibody. Leukemia 2008; 22: 42-48. J Chemother 2009; 21: 666-672. [119] Moura IC, Lepelletier Y, Arnulf B, England P, [107] Kukulj S, Jaganjac M, Boranic M, Krizanac S, Baude C, Beaumont C, Bazarbachi A, Benham- Santic Z, Poljak-Blazi M. Altered iron metabo- ou M, Monteiro RC, Hermine O. A neutralizing lism, inflammation, transferrin receptors, and monoclonal antibody (mAb A24) directed ferritin expression in non-small-cell lung can- against the transferrin receptor induces apop- cer. Med Oncol 2010; 27: 268-277. tosis of tumor T lymphocytes from ATL patients. [108] Ferrando AA, López-Otín C. Clonal evolution in Blood 2004; 103: 1838-1845. leukemia. Nat Med 2017; 23: 1135-1145. [120] Schaar DG, Medina DJ, Moore DF, Strair RK, [109] Taetle R, Rhyner K, Castagnola J, To D, Men- Ting Y. miR-320 targets transferrin receptor 1 delsohn J. Role of transferrin, Fe, and transfer- (CD71) and inhibits cell proliferation. Exp He- rin receptors in myeloid leukemia cell growth. matol 2009; 37: 245-255. Studies with an antitransferrin receptor mono- [121] Camp ER, Wang C, Little EC, Watson PM, Pirol- clonal antibody. J Clin Invest 1985; 75: 1061- lo KF, Rait A, Cole DJ, Chang EH, Watson DK. 1067. Transferrin receptor targeting nanomedicine [110] Scott CS, Ramsden W, Limbert HJ, Master PS, delivering wild-type p53 gene sensitizes pan- Roberts BE. Membrane transferrin receptor creatic cancer to gemcitabine therapy. Cancer (TfR) and nuclear proliferation-associated Ki- Gene Ther 2013; 20: 222-228. 67 expression in hemopoietic malignancies. [122] Daniels-Wells TR, Widney DP, Leoh LS, Mar- Leukemia 1988; 2: 438-442. tínez-Maza O, Penichet ML. Efficacy of an anti- [111] Liu Q, Wang M, Hu Y, Xing H, Chen X, Zhang Y, transferrin receptor 1 antibody against aids- Zhu P. Significance of CD71 expression by flow related non-hodgkin lymphoma: a brief com- cytometry in diagnosis of acute leukemia. Leuk munication. J Immunother 2015; 38: 307-310. Lymphoma 2014; 55: 892-898. [123] Shimosaki S, Nakahata S, Ichikawa T, Kitana- [112] Płoszyńska A, Ruckemann-Dziurdzińska K, ka A, Kameda T, Hidaka T, Kubuki Y, Kurosawa Jóźwik A, Mikosik A, Lisowska K, Balcerska A, G, Zhang L, Sudo Y, Shimoda K, Morishita K. Witkowski JM. Cytometric evaluation of trans- Development of a complete human IgG mono- ferrin receptor 1 (CD71) in childhood acute clonal antibody to transferrin receptor 1 tar- lymphoblastic leukemia. Folia Histochem Cyto- geted for adult T-cell leukemia/lymphoma. Bio- biol 2012; 50: 304-311. chem Biophys Res Commun 2017; 485: [113] Pham DH, Powell JA, Gliddon BL, Moretti PA, 144-151. Tsykin A, Van der Hoek M, Kenyon R, Goodall [124] Yu H, Guo P, Xie X, Wang Y, Chen G. Ferroptosis, GJ, Pitson SM. Enhanced expression of trans- a new form of cell death, and its relationships ferrin receptor 1 contributes to oncogenic sig- with tumourous diseases. J Cell Mol Med nalling by sphingosine kinase 1. Oncogene 2017; 21: 648-657. 2014; 33: 5559-5568. [125] Zhou Z, Song J, Tian R, Yang Z, Yu G, Lin L, [114] Bayeva M, Khechaduri A, Puig S, Chang HC, Pa- Zhang G, Fan W, Zhang F, Niu G, Nie L, Chen X. tial S, Blackshear PJ, Ardehali H. mTOR regu- Activatable singlet oxygen generation from lip- lates cellular iron homeostasis through tristet- id hydroperoxide nanoparticles for cancer ther- raprolin. Cell Metab 2012; 16: 645-657. apy. Angew Chem Int Ed Engl 2017; 56: 6492- [115] O’Donnell KA, Yu D, Zeller KI, Kim JW, Racke F, 6496. Thomas-Tikhonenko A, Dang CV. Activation of [126] Aldahoun MA, Jaafar MS, Al-Akhras MH, Bou- transferrin receptor 1 by c-Myc enhances cel- oudina M. Enhanced nanocurcumin toxicity lular proliferation and tumorigenesis. Mol Cell against (PC3) tumor and microbial by using Biol 2006; 26: 2373-2386. magnetic field in vitro. Artif Cells Nanomed Bio- [116] Jiao Y, Wilkinson J, Christine PE, Buss JL, Wang technol 2017; 45: 843-853. W, Planalp R, Torti FM, Torti SV. Iron chelation [127] Liu Z, Zhan X, Yang M, Yang Q, Xu X, Lan F, Wu in the biological activity of curcumin. Free Rad- Y, Gu Z. A magnetic-dependent protein corona ic Biol Med 2006; 40: 1152-1160. of tailor-made superparamagnetic iron oxides [117] Yang C, Ma X, Wang Z, Zeng X, Hu Z, Ye Z, Shen alters their biological behaviors. Nanoscale G. Curcumin induces apoptosis and protective 2016; 8: 7544-7555. autophagy in castration-resistant prostate can- cer cells through iron chelation. Drug Des Dev- el Ther 2017; 11: 431-439.

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