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Ferroptosis, a New Form of Cell Death: Opportunities and Challenges In Mou et al. Journal of Hematology & Oncology (2019) 12:34 https://doi.org/10.1186/s13045-019-0720-y REVIEW Open Access Ferroptosis, a new form of cell death: opportunities and challenges in cancer Yanhua Mou1,2†, Jun Wang2†, Jinchun Wu1, Dan He3, Chunfang Zhang4, Chaojun Duan1,2,5* and Bin Li1,2* Abstract Ferroptosis is a novel type of cell death with distinct properties and recognizing functions involved in physical conditions or various diseases including cancers. The fast-growing studies of ferroptosis in cancer have boosted a perspective for its usage in cancer therapeutics. Here, we review the current findings of ferroptosis regulation and especially focus on the function of ncRNAs in mediating the process of cell ferroptotic death and on how ferroptosis was in relation to other regulated cell deaths. Aberrant ferroptosis in diverse cancer types and tissues were summarized, and we elaborated recent data about the novel actors of some “conventional” drugs or natural compounds as ferroptosis inducers in cancer. Finally, we deliberate future orientation for ferroptosis in cancer cells and current unsettled issues, which may forward the speed of clinical use of ferroptosis induction in cancer treatment. Keywords: Ferroptosis, Apoptosis, Autophagy, NcRNAs, Cancers, P53 Background between thiols and catalytic iron, ferroptosis does not Ferroptosis was first proposed by Dixon as a novel cell often happen in the cancer development [10]. The under- death in 2012 [1]. Unlike autophagy and apoptosis, fer- lying molecular mechanisms remain poorly understood. roptosis is an iron-dependent and reactive oxygen species We herein review the occurrence and regulation of ferrop- (ROS)-reliant cell death with characteristics mainly of tosis in various cancer cells. The opportunity and chal- cytological changes, including decreased or vanished lenge of cancer treatment based on ferroptosis will be mitochondria cristae, a ruptured outer mitochondrial detailed, which was desired to prosper new strategies for membrane, and a condensed mitochondrial membrane cancer therapy of clinical value. [2–6]. These cell abnormalities resulted from the loss of selective permeability of plasma membrane due to in- tense membrane lipid peroxidation and the occurrence Ferroptosis, from a cancer perspective: an overview of oxidative stress (Table 1)[7]. Ferroptosis was first observed in oncogenic Researches indicated that ferroptosis could be triggered Ras-expressing human foreskin fibroblast cell line by a by diverse physiological conditions and pathological battery of small compounds considered as ferroptosis-in- stresses in humans and animals [8].Ferroptosisisgrad- ducing agents (FIN), including erastin and Ras-selective le- ually accepted as an adaptive feature to eliminate the ma- thal small molecule 3 (RSL 3). With the following studies, lignant cells. It plays a pivotal role in the depression of the relationship of Ras oncoprotein with ferroptosis be- tumorigenesis by removing the cells that are deficient in comes agnostic. Some Ras WT cells including fibrosar- key nutrients in the environment or damaged by infection coma cells, kidney tubule cells, and T cells are vulnerable or ambient stress [9]. Studies have shown that the classic to erastin, but the RMS13 rhabdomyosarcoma cells with oxidative stress pathway was an important causative factor Ras mutation were resistant to erastin and RLS3. Indeed, to induce ferroptosis. Although cancer cells are under the ferroptosis inducer artesunate/erastin can promote continuous oxidative stress with an exquisite balance ferroptosis in a Ras-reliant way in pancreatic cancer or transformed fibroblastic cells, while in a Ras-independent * Correspondence: [email protected]; [email protected] manner in leukemia cells [6, 11]. † Yanhua Mou and Jun Wang contributed equally to this work. Emerging evidence implicated that ferroptosis may be 1Department of Oncology, Xiangya Hospital, Central South University, Changsha 410008, People’s Republic of China an adaptive process which was critical for eradicating Full list of author information is available at the end of the article the carcinogenic cells [1]. More clues for this role of © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Mou et al. Journal of Hematology & Oncology (2019) 12:34 Page 2 of 16 Table 1 The main features of ferroptosis, apoptosis, autophagy, necroptosis, and pyroptosis Cell death Ferroptosis Apoptosis Autophagy Necroptosis Pyroptosis Biochemical Inhibition of xCT and Activation of caspases Increased lysosomal Drop in ATP Dependent on features reduced GSH, inhibition oligonucleosomal activity levels; activation caspase-1 and of GPX4. Iron accumulation DNA fragmentation of RIP1, RIP3, and MLKL proinflammatory and lipid peroxidation cytokine releases Morphological Small mitochondria with Plasma membrane Formation of double- Plasma membrane Karyopyknosis, features condensed mitochondrial blebbing; cellular and membraned rupture; organelle cell edema and membrane densities, nuclear volume autolysosomes swelling; moderate membrane reduction or vanishing of reduction; nuclear chromatin condensation rupture mitochondria crista, as well fragmentation as outer mitochondrial membrane rupture Key genes GPX4, Nrf2, LSH, TFR1, xCT Caspase, P53, Fas, ATG5, ATG7, DRAM3, LEF1, RIP1, RIP3 Caspase-1, IL-1β, Bcl-2, Bax TFEB IL-18 Regulatory xCT and Gpx4, MVA, HSF1- Death receptor, PI3K-AKT- TNFα,TNFR1,TLR3, Caspase-1, pathways HSPB1, p62-Keap1-Nrf2 Mitochondrial, mTOR,MAPK-ERK1/2- TRAIL, FasL, ROS, NLRP3-mediated pathway, LSH signal Endoplasmic mTOR signal pathway PKC-MAPK-AP-1-mediated signaling pathway. pathway reticulum pathway signaling pathway Csapase, P53, Bcl-2 mediated signaling pathway Released DAMP HMGB1 Ecto-CRT, HMGB1, HMGB-1 DNA and IL-6 HMGB1, ATP, and ATP IL-1β, and IL-18 Immune features Pro-inflammatory Mostly anti- Mostly anti- Mostly pro-inflammatory pro-inflammatory inflammatory inflammatory Inducers Erastin,DPI2, BSO, SAS, FASL, DCC, UNC5B Rapamycin, lithium, TNFa, zVAD-fmk, ZnO—NPs, lanperisone, SRS, RSL3, sodium, PAMPS Ivermectin DPI7, DPI10, FIN56, valproate, sorafenib, artemisinin carbamazepine, C2-ceramide, rapamycin Inhibitors Desferoxamine, vitamin E, XIAP, c-IAP1, c-IAP2, 3-ME, LY294002, Nec-1, NSA, Necrosulfonami-de U0126, ferrostatin-1, ILP-2, ML-IAP/livin, wortmannin, PIK-III, Kongensin- A SRS, CA-1, cycloheximide, NAIP, compound 31, SAR aminooxyacetic acid Z-VADFMK 405, Vps34- Liproxstatin-1 HCl In1,MRT68921, Spautin-1, Bafilomycin A1, hydrochloroquin ferroptosis can be derived from recent researches of the Ferroptosis is programmed necrosis mainly triggered by tumor suppressor P53 (TP53). The acetylation-defective extra-mitochondrial lipid peroxidation arising from an mutant TP533KR lost the ability to induce cell senes- iron-dependent ROS accretion. Excessive iron originally cence, apoptosis, and cell-cycle arrest, which were the from aberrant iron metabolism or maladjustment of two main functions of TP53 in tumor suppression. Impres- major redox systems (lipid peroxidation and thiols) was sively, TP533KR can still hold the capacity of inhibiting the main incentive factors of ROS production. Glutathione tumorigenesis due to its ferroptosis induction [12–14]. (GSH), a thiol-containing tripeptide, synthesis is deter- An argument does emerge that P53 expression may pro- mined by the constant import of cysteine (Cys2) by the mote, limit, or detain the outset of ferroptosis in certain cell surface Cys2/glutamate antiporter xCT (Fig. 2). cells or conditions (Fig. 1). These opposite jobs of p53 in The activation of Ras-mitogen-activated protein kinase operating the process of ferroptotic cell death were exe- (MEK) signaling can attribute to the sensitivity of cancer cuted by different mechanisms, including effects on cells to ferroptosis, resulting from its promoting iron abun- metabolic genes transcription, post-translational regula- dance in cancer by governing the expression levels of the tion or by virtue of P53-P21 axis [15, 16]. The bidirec- transferrin receptor and ferritin [2, 7, 8]. And the overactive tional regulation of ferroptosis by P53 in a cell-specific Ras-MEK pathway may enhance ROS generation via or context-dependent manner needs to be further inves- inhibiting cystine (Cys2) uptake or mitochondrial tigated. Moreover, it is still obscure that what kind of voltage-dependent anion channel 2/3 (VDAC 2/3) and con- role P53-target genes take part in manipulating of the sequently sensitize cancercellstoferroptosis[18, 19]. But ferroptotic cell death [17]? scientist and skeptics argued that the conclusion is Mou et al. Journal of Hematology & Oncology (2019) 12:34 Page 3 of 16 Fig. 1 P53 regulate ferroptosis. P533KR cannot elicit apoptosis activity, it retains the ability to promote ferroptosis. GLS2 and SAT1 contribute, at least in part, to P533KR-mediated ferroptosis. P533KR completely retains the ability to regulate the expression of SLC7A11. Interestingly, WTP53 inhibits
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