DOCSLIB.ORG

2. the Hippo Pathway Effector TAZ Regulates Ferroptosis in Renal Cell Carcinoma

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
2. the Hippo Pathway Effector TAZ Regulates Ferroptosis in Renal Cell Carcinoma Molecular Mechanisms of TAZ-regulating Ferroptosis in Cancer Cells and tRNA Fragment in Erythrocytes by Wen-Hsuan Yang Department of Biochemistry Duke University Date:_______________________ Approved: ___________________________ Jen-Tsan Ashley Chi, Supervisor ___________________________ Kate Meyer ___________________________ Margarethe Kuehn ___________________________ Perry Blackshear Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Biochemistry in the Graduate School of Duke University 2019 ABSTRACT Molecular Mechanisms of TAZ-regulating Ferroptosis in Cancer Cells and tRNA Fragment in Erythrocytes by Wen-Hsuan Yang Department of Biochemistry Duke University Date:_______________________ Approved: ___________________________ Jen-Tsan Ashley Chi, Supervisor ___________________________ Kate Meyer ___________________________ Margarethe Kuehn ___________________________ Perry Blackshear An abstract of a dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Biochemistry in the Graduate School of Duke University 2019 Copyright by Wen-Hsuan Yang 2019 Abstract Here, I sought to determine the molecular mechanisms of the cellular response to stresses in two contexts. In the first part of my thesis, I focus on how ferroptosis, a lipid oxidative stress-induced cell death, can be regulated by cell density via an evolutionarily conserved pathway effector. In the second part, I focus on the transcriptional response of red blood cells (RBCs) during the refrigerated storage. Ferroptosis is a novel form of programmed cell death characterized by the accumulation of lipid peroxidation. It can be induced by the oxidative stress caused by starvation of cystine, inhibition of glutathione peroxidase 4, or activation of NADPH oxidase(s). The canonical ferroptosis inducer, erastin, is a small molecule which triggers oxidative stress by inhibiting the cystine-glutamate transporter (xCT) and thus reduces intracellular cysteine level and glutathione biosynthesis. Recent studies indicate ferroptosis may have therapeutic potential toward cancer. However, much remains unknown about the determinants of ferroptosis susceptibility. We observed that vulnerability to the ferroptosis of cancer cells is highly influenced by cell confluency. Since cell density can be sensed by the evolutionarily conserved Hippo pathway effectors, YAP/TAZ, we hypothesize if these Hippo pathway effectors are involved in erastin-induced ferroptosis response. My data show that TAZ, instead of YAP, is abundantly expressed in both renal and ovarian cancer cells and undergoes density- iv dependent nuclear/cytosolic translocation. TAZ removal confers ferroptosis resistance, while overexpression of constitutively active form of TAZ, TAZS89A, sensitizes cells to ferroptosis. Similarly, I found that a lower TAZ level in the recurrent ovarian cancer is responsible for reduced ferroptosis susceptibility of these cells. I further investigated the mechanisms by which TAZ regulates ferroptosis. and found that TAZ regulates ferroptosis through EMP1-NOX4 axis in renal cancers and ANGPTL4-NOX2 axis in ovarian cancers. The relevance of the Hippo pathway effector with ferroptosis suggests that ferroptosis-inducing agents may be used to target the TAZ-activated tumors. The second part of my dissertation investigated the molecular mechanisms of transcriptome changes inside RBCs during ex vivo storages. RBCs are the major component of blood transfusions, one of the most common procedures in the hospital. In addition, some athletes utilize blood transfusion of stored RBCs to increase athletic performance, a practice banned by the world anti-doping agency. Currently, RBCs can be stored for up to 42 days at ~4°C before transfusion. However, transfusion with RBCs after long storage duration may correlate with a poorer prognosis compared with fresh RBCs and results in increased morbidity and mortality. To recognize the undesirable effects of prolonged RBC storage on transfusion recipients, it is critical to understand storage-associated RBC changes. To this end, our lab has previously identified a variety of RNA species in mature RBCs and profiled the miRNA changes that occur in RBCs at v different time intervals during in vitro storage. This profiling demonstrates that the abundance of most RBC miRNAs did not change significantly during the 42 days of refrigerated storage, indicating extremely long decay half-lives. Unexpectedly, miR-720, a cleavage product of tRNAThr, increased dramatically in the first two weeks and persisted during storage. Furthermore, I present evidence for a role of angiogenin in tRNA cleavage to generate miR-720 during RBC storage. The dramatic increase in miR- 720 may be used to monitor transfused RBCs in clinical patients, athletes performing blood doping, and other settings. Additionally, the increase in miR-720 levels in the stored RBC may potentially contribute to the cellular and clinical phenotypes associated with storage lesions. Taken together, these studies on how human cells respond to stresses have the potentials as guidance for cancer patients toward ferroptosis-inducing chemotherapeutics or provide a novel way of detecting blood doping or understanding the RBC storage lesions. vi Dedication To my parents, my brother, my husband, and my nephews for all their love, support, and encouragement. vii Contents Abstract ......................................................................................................................................... iv Dedication ................................................................................................................................... vii List of Tables .............................................................................................................................. xiii List of Figures .............................................................................................................................xiv List of Abbreviations ................................................................................................................. xix 1. Introduction ............................................................................................................................... 1 1.1 Ferroptosis ......................................................................................................................... 3 1.2 Hippo signaling pathway ................................................................................................ 4 2. The Hippo Pathway Effector TAZ Regulates Ferroptosis in Renal Cell Carcinoma ....... 6 2.1 Introduction ....................................................................................................................... 6 2.2 Methods ............................................................................................................................. 9 2.2.1 Materials and reagents ................................................................................................ 9 2.2.2 Cell culture and transfection ...................................................................................... 9 2.2.3 siRNA-mediated gene knockdown ......................................................................... 10 2.2.4 Cell viability assays ................................................................................................... 10 2.2.5 Western blot analysis ................................................................................................ 11 2.2.6 RNA isolation and quantitative real-time PCR ..................................................... 11 2.2.7 Microarray .................................................................................................................. 12 2.2.8 Generation of patient-derived xenograft (PDX) and cell lines ............................ 13 2.2.9 Immunofluorescence staining ................................................................................. 14 viii 2.2.10 Chromatin immunoprecipitation (ChIP) analysis .............................................. 14 2.2.11 Lipid ROS assay using flow cytometry ................................................................ 16 2.2.12 Statistical analyses ................................................................................................... 16 2.3 Results .............................................................................................................................. 17 2.3.1 Cell density affects the sensitivity of RCC cell lines to erastin-induced ferroptosis ............................................................................................................................ 17 2.3.2 TAZ regulates sensitivity to erastin-induced ferroptosis .................................... 29 2.3.3 EMP1 is a direct target gene of TAZ that regulates ferroptosis sensitivity ....... 38 2.3.4 EMP1 regulates ferroptosis through NOX4 ........................................................... 49 2.4 Discussion ........................................................................................................................ 58 3. A TAZ-ANGPTL4-NOX2 axis regulates ferroptotic cell death and chemoresistance in epithelial ovarian cancer ............................................................................................................ 63 3.1 Introduction ....................................................................................................................
Load more

Recommended publications
  • Effective Ferroptotic Small-Cell Lung Cancer Cell Death from SLC7A11 Inhibition by Sulforaphane
    ONCOLOGY LETTERS 21: 71, 2021 Effective ferroptotic small-cell lung cancer cell death from SLC7A11 inhibition by sulforaphane YUKO IIDA1*, MAYUMI OKAMOTO-KATSUYAMA1*, SHUICHIRO MARUOKA1, KENJI MIZUMURA1, TETSUO SHIMIZU1, SOTARO SHIKANO1, MARI HIKICHI1, MAI TAKAHASHI1, KOTA TSUYA1, SHINICHI OKAMOTO1, TOSHIO INOUE1, YOKO NAKANISHI2, NORIAKI TAKAHASHI1, SHINOBU MASUDA2, SHU HASHIMOTO1,3 and YASUHIRO GON1 1Division of Respiratory Medicine, Department of Internal Medicine; 2Division of Oncologic Pathology, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo 173-8610; 3Shonan University of Medical Science, Kanagawa 244-0806, Japan Received October 20, 2019; Accepted October 14, 2020 DOI: 10.3892/ol.2020.12332 Abstract. Small-cell lung cancer (SCLC) is a highly aggres- lower in SFN-treated cells compared with that in the control sive cancer with poor prognosis, due to a lack of therapeutic cells (P<0.0001 and P=0.0006, respectively). These results targets. Sulforaphane (SFN) is an isothiocyanate derived indicated that the anticancer effects of SFN may be caused from cruciferous vegetables and has shown anticancer effects by ferroptosis in the SCLC cells, which was hypothesized against numerous types of cancer. However, its anticancer to be triggered from the inhibition of mRNA and protein effect against SCLC remains unclear. The present study aimed expression levels of SLC7A11. In conclusion, the present study to demonstrate the anticancer effects of SFN in SCLC cells by demonstrated that SFN-induced cell death was mediated via investigating cell death (ferroptosis, necroptosis and caspase ferroptosis and inhibition of the mRNA and protein expression inhibition). The human SCLC cell lines NCI-H69, NCI-H69AR levels of SLC7A11 in SCLC cells.
    [Show full text]
  • O-Glcnacylated C-Jun Antagonizes Ferroptosis Via Inhibiting GSH Synthesis in Liver Cancer T
    Cellular Signalling 63 (2019) 109384 Contents lists available at ScienceDirect Cellular Signalling journal homepage: www.elsevier.com/locate/cellsig O-GlcNAcylated c-Jun antagonizes ferroptosis via inhibiting GSH synthesis in liver cancer T Yan Chena, Guoqing Zhua, Ya Liua,QiWua, Xiao Zhangb, Zhixuan Bianc, Yue Zhangd, ⁎ ⁎ Qiuhui Panc, , Fenyong Suna, a Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China b Shanghai Institute of Thoracic Tumors, Shanghai Chest Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200030, China c Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China d Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China ARTICLE INFO ABSTRACT Keywords: Ferroptosis is a metabolism-related cell death. Stimulating ferroptosis in liver cancer cells is a strategy to treat Erastin liver cancer. However, how to eradicate liver cancer cells through ferroptosis and the obstacles to inducing O-GlcNAcylation ferroptosis in liver cancer remain unclear. Here, we observed that erastin suppressed the malignant phenotypes Phosphorylation of liver cancer cells by inhibiting O-GlcNAcylation of c-Jun and further inhibited protein expression, tran- Glutathione scription activity and nuclear accumulation of c-Jun. Overexpression of c-Jun-WT with simultaneous PuGNAc Transcription treatment conversely inhibited erastin-induced ferroptosis, whereas overexpression of c-Jun-WT alone or Promoter overexpression of c-Jun-S73A (a non-O-GlcNAcylated form of c-Jun) with PuGNAc treatment did not exert a similar effect. GSH downregulation induced by erastin was restored by overexpression of c-Jun-WT with si- multaneous PuGNAc treatment.
    [Show full text]
  • Ferroptosis: Mechanisms and Links with Diseases
    Signal Transduction and Targeted Therapy www.nature.com/sigtrans REVIEW ARTICLE OPEN Ferroptosis: mechanisms and links with diseases Hong-fa Yan1, Ting Zou2, Qing-zhang Tuo1, Shuo Xu1,2, Hua Li2, Abdel Ali Belaidi 3 and Peng Lei1 Ferroptosis is an iron-dependent cell death, which is different from apoptosis, necrosis, autophagy, and other forms of cell death. The process of ferroptotic cell death is defined by the accumulation of lethal lipid species derived from the peroxidation of lipids, which can be prevented by iron chelators (e.g., deferiprone, deferoxamine) and small lipophilic antioxidants (e.g., ferrostatin, liproxstatin). This review summarizes current knowledge about the regulatory mechanism of ferroptosis and its association with several pathways, including iron, lipid, and cysteine metabolism. We have further discussed the contribution of ferroptosis to the pathogenesis of several diseases such as cancer, ischemia/reperfusion, and various neurodegenerative diseases (e.g., Alzheimer’s disease and Parkinson’s disease), and evaluated the therapeutic applications of ferroptosis inhibitors in clinics. Signal Transduction and Targeted Therapy (2021) ;6:49 https://doi.org/10.1038/s41392-020-00428-9 INTRODUCTION Ferroptosis can be prevented by using iron chelators (e.g., Ferroptosis is a newly identified iron-dependent cell death that is deferoxamine), whereas supplying exogenous iron (e.g., ferric different from other cell death forms, including apoptosis and ammonium citrate) enhances ferroptosis.1,7 Several studies have 1234567890();,: necrosis. The program involves three primary metabolisms shown that the regulation of genes related to iron metabolism can involving thiol, lipid, and iron, leading to an iron-dependent also regulate ferroptotic cell death, such as transferrin, nitrogen generation of lipid peroxidation and, ultimately, cell death.
    [Show full text]
  • Programmed Cell-Death by Ferroptosis: Antioxidants As Mitigators
    International Journal of Molecular Sciences Review Programmed Cell-Death by Ferroptosis: Antioxidants as Mitigators Naroa Kajarabille 1 and Gladys O. Latunde-Dada 2,* 1 Nutrition and Obesity Group, Department of Nutrition and Food Sciences, University of the Basque Country (UPV/EHU), 01006 Vitoria, Spain; [email protected] 2 King’s College London, Department of Nutritional Sciences, Faculty of Life Sciences and Medicine, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK * Correspondence: [email protected] Received: 9 September 2019; Accepted: 2 October 2019; Published: 8 October 2019 Abstract: Iron, the fourth most abundant element in the Earth’s crust, is vital in living organisms because of its diverse ligand-binding and electron-transfer properties. This ability of iron in the redox cycle as a ferrous ion enables it to react with H2O2, in the Fenton reaction, to produce a hydroxyl radical ( OH)—one of the reactive oxygen species (ROS) that cause deleterious oxidative damage • to DNA, proteins, and membrane lipids. Ferroptosis is a non-apoptotic regulated cell death that is dependent on iron and reactive oxygen species (ROS) and is characterized by lipid peroxidation. It is triggered when the endogenous antioxidant status of the cell is compromised, leading to lipid ROS accumulation that is toxic and damaging to the membrane structure. Consequently, oxidative stress and the antioxidant levels of the cells are important modulators of lipid peroxidation that induce this novel form of cell death. Remedies capable of averting iron-dependent lipid peroxidation, therefore, are lipophilic antioxidants, including vitamin E, ferrostatin-1 (Fer-1), liproxstatin-1 (Lip-1) and possibly potent bioactive polyphenols.
    [Show full text]
  • Involvement of NDPK-B in Glucose Metabolism-Mediated Endothelial Damage Via Activation of the Hexosamine Biosynthesis Pathway and Suppression of O-Glcnacase Activity
    cells Article Involvement of NDPK-B in Glucose Metabolism-Mediated Endothelial Damage via Activation of the Hexosamine Biosynthesis Pathway and Suppression of O-GlcNAcase Activity 1, 1, 2 1 Anupriya Chatterjee y, Rachana Eshwaran y, Gernot Poschet , Santosh Lomada , Mahmoud Halawa 1, Kerstin Wilhelm 3, Martina Schmidt 4,5 , Hans-Peter Hammes 6, Thomas Wieland 1,7 and Yuxi Feng 1,* 1 Experimental Pharmacology Mannheim, European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany; [email protected] (A.C.); [email protected] (R.E.); [email protected] (S.L.); [email protected] (M.H.); [email protected] (T.W.) 2 Centre for Organismal Studies (COS), 69120 Heidelberg, Germany; [email protected] 3 Angiogenesis & Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany; [email protected] 4 Department of Molecular Pharmacology, University of Groningen, 9713 AV Groningen, The Netherlands; [email protected] 5 Groningen Research Institute for Asthma and COPD, GRIAC, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands 6 5th Medical Clinic, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany; [email protected] 7 DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany * Correspondence: [email protected]; Tel.: +49-621-383-71762; Fax: +49-621-383-71750 These authors contributed equally. y Received: 27 August 2020; Accepted: 13 October 2020; Published: 19 October 2020 Abstract: Our previous studies identified that retinal endothelial damage caused by hyperglycemia or nucleoside diphosphate kinase-B (NDPK-B) deficiency is linked to elevation of angiopoietin-2 (Ang-2) and the activation of the hexosamine biosynthesis pathway (HBP).
    [Show full text]
  • Ferroptosis-Related Flavoproteins: Their Function and Stability
    International Journal of Molecular Sciences Review Ferroptosis-Related Flavoproteins: Their Function and Stability R. Martin Vabulas Charité-Universitätsmedizin, Institute of Biochemistry, Charitéplatz 1, 10117 Berlin, Germany; [email protected]; Tel.: +49-30-4505-28176 Abstract: Ferroptosis has been described recently as an iron-dependent cell death driven by peroxida- tion of membrane lipids. It is involved in the pathogenesis of a number of diverse diseases. From the other side, the induction of ferroptosis can be used to kill tumor cells as a novel therapeutic approach. Because of the broad clinical relevance, a comprehensive understanding of the ferroptosis-controlling protein network is necessary. Noteworthy, several proteins from this network are flavoenzymes. This review is an attempt to present the ferroptosis-related flavoproteins in light of their involvement in anti-ferroptotic and pro-ferroptotic roles. When available, the data on the structural stability of mutants and cofactor-free apoenzymes are discussed. The stability of the flavoproteins could be an important component of the cellular death processes. Keywords: flavoproteins; riboflavin; ferroptosis; lipid peroxidation; protein quality control 1. Introduction Human flavoproteome encompasses slightly more than one hundred enzymes that par- ticipate in a number of key metabolic pathways. The chemical versatility of flavoproteins relies on the associated cofactors, flavin mononucleotide (FMN) and flavin adenine dinu- cleotide (FAD). In humans, flavin cofactors are biosynthesized from a precursor riboflavin that has to be supplied with food. To underline its nutritional essentiality, riboflavin is called vitamin B2. In compliance with manifold cellular demands, flavoproteins have been accommo- Citation: Vabulas, R.M. dated to operate at different subcellular locations [1].
    [Show full text]
  • Drugs Repurposed As Antiferroptosis Agents Suppress Organ Damage, Including AKI, by Functioning As Lipid Peroxyl Radical Scavengers
    BASIC RESEARCH www.jasn.org Drugs Repurposed as Antiferroptosis Agents Suppress Organ Damage, Including AKI, by Functioning as Lipid Peroxyl Radical Scavengers Eikan Mishima ,1 Emiko Sato,1,2 Junya Ito,3 Ken-ichi Yamada,4 Chitose Suzuki,1 Yoshitsugu Oikawa,5 Tetsuro Matsuhashi,5 Koichi Kikuchi,1 Takafumi Toyohara,1 Takehiro Suzuki,1 Sadayoshi Ito,1,6 Kiyotaka Nakagawa,3 and Takaaki Abe 1,7,8 Due to the number of contributing authors, the affiliations are listed at the end of this article. ABSTRACT Background Ferroptosis, nonapoptotic cell death mediated by free radical reactions and driven by the oxidative degradation of lipids, is a therapeutic target because of its role in organ damage, including AKI. Ferroptosis-causing radicals that are targeted by ferroptosis suppressors have not been unequivocally iden- tified. Because certain cytochrome P450 substrate drugs can prevent lipid peroxidation via obscure mecha- nisms, we evaluated their antiferroptotic potential and used them to identify ferroptosis-causing radicals. Methods Using a cell-based assay, we screened cytochrome P450 substrate compounds to identify drugs with antiferroptotic activity and investigated the underlying mechanism. To evaluate radical-scavenging activity, we used electron paramagnetic resonance–spin trapping methods and a fluorescence probe for lipid radicals, NBD-Pen, that we had developed. We then assessed the therapeutic potency of these drugs in mouse models of cisplatin-induced AKI and LPS/galactosamine-induced liver injury. Results We identified various US Food and Drug Administration–approved drugs and hormones that have antiferroptotic properties, including rifampicin, promethazine, omeprazole, indole-3-carbinol, carvedilol, pro- pranolol, estradiol, and thyroid hormones.
    [Show full text]
  • Ferroptosis: Mechanisms, Biology and Role in Disease
    REVIEWS Ferroptosis: mechanisms, biology and role in disease Xuejun Jiang 1 ✉ , Brent R. Stockwell 2,3 ✉ and Marcus Conrad 4,5 ✉ Abstract | The research field of ferroptosis has seen exponential growth over the past few years, since the term was coined in 2012. This unique modality of cell death, driven by iron-dependent phospholipid peroxidation, is regulated by multiple cellular metabolic pathways, including redox homeostasis, iron handling, mitochondrial activity and metabolism of amino acids, lipids and sugars, in addition to various signalling pathways relevant to disease. Numerous organ injuries and degenerative pathologies are driven by ferroptosis. Intriguingly, therapy-resistant cancer cells, particularly those in the mesenchymal state and prone to metastasis, are exquisitely vulnerable to ferroptosis. As such, pharmacological modulation of ferroptosis, via both its induction and its inhibition, holds great potential for the treatment of drug-resistant cancers, ischaemic organ injuries and other degenerative diseases linked to extensive lipid peroxidation. In this Review, we provide a critical analysis of the current molecular mechanisms and regulatory networks of ferroptosis, the potential physiological functions of ferroptosis in tumour suppression and immune surveillance, and its pathological roles, together with a potential for therapeutic targeting. Importantly, as in all rapidly evolving research areas, challenges exist due to misconceptions and inappropriate experimental methods. This Review also aims to address these issues and to provide practical guidelines for enhancing reproducibility and reliability in studies of ferroptosis. Finally, we discuss important concepts and pressing questions that should be the focus of future ferroptosis research. Cells represent the fundamental organizing unit of and intercellular contacts, as well as oncogenic and life.
    [Show full text]
  • Ferroptosis Response Segregates Small Cell Lung Cancer (SCLC) Neuroendocrine Subtypes
    bioRxiv preprint doi: https://doi.org/10.1101/2020.07.11.198408; this version posted July 11, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Ferroptosis response segregates small cell lung cancer (SCLC) neuroendocrine subtypes Authors: Christina M. Bebber1,2,3, Emily S. Thomas1,2,4, Zhiyi Chen1,2, Jenny Stroh1,2, Ariadne Androulidaki1,2, Anna Schmitt2,3, Michaela N. Höhne2,5, Lukas Stüker1,2, Cleidson de Pádua Alves1, Armin Khonsari1,6,7, Marcel A. Dammert1,6,7, Fatma Parmaksiz1,6,7, Filippo Beleggia3, Martin L. Sos1,6,7, Jan Riemer2,5, Julie George1, Susanne Brodesser2, Roman K. Thomas1,6,8, H. Christian Reinhardt2,3,7, and Silvia von Karstedt1,2,7, * Affiliations: 1Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, Germany. 2CECAD Cluster of Excellence, University of Cologne, Cologne, Germany. 3Clinic I for Internal Medicine, Medical Faculty, University Hospital of Cologne, Cologne, Germany. 4Imperial College London, London, United Kingdom. 5Department for Chemistry, Institute for Biochemistry, University of Cologne, Cologne, Germany. 6Institute of Pathology, Medical Faculty, University Hospital of Cologne, Cologne, Germany. 7Center for Molecular Medicine Cologne, Medical Faculty, University Hospital of Cologne, Cologne, Germany. 8DKFZ, German Cancer Research Center, German Cancer Consortium (DKTK), Heidelberg, Germany. *To whom correspondence should be addressed: Silvia von Karstedt, Email: s.vonkarstedt@uni- koeln.de One Sentence Summary: The SCLC non-neuroendocrine subtype is sensitive to ferroptosis bioRxiv preprint doi: https://doi.org/10.1101/2020.07.11.198408; this version posted July 11, 2020.
    [Show full text]
  • HSPA5 Regulates Ferroptotic Cell Death in Cancer Cells Shan Zhu1,2,3, Qiuhong Zhang4, Xiaofan Sun1, Herbert J
    Published OnlineFirst January 27, 2017; DOI: 10.1158/0008-5472.CAN-16-1979 Cancer Therapeutics, Targets, and Chemical Biology Research HSPA5 Regulates Ferroptotic Cell Death in Cancer Cells Shan Zhu1,2,3, Qiuhong Zhang4, Xiaofan Sun1, Herbert J. Zeh III4, Michael T. Lotze4, Rui Kang4, and Daolin Tang1,2,3,4 Abstract Ferroptosis is a form of regulated cell death driven by oxidation. Importantly, the HSPA5–GPX4 pathway mediated oxidative injury promoting lipid peroxidation, although ferroptosis resistance, limiting the anticancer activity of gemci- detailed molecular regulators are largely unknown. Here, we tabine. Genetic or pharmacologic inhibition of the HSPA5– show that heatshock 70-kDa protein 5 (HSPA5) negatively GPX4 pathway enhanced gemcitabine sensitivity by disinhibit- regulates ferroptosis in human pancreatic ductal adenocarci- ing ferroptosis in vitro and in both subcutaneous and ortho- noma (PDAC) cells. Mechanistically, activating transcription topic animal models of PDAC. Collectively, these findings factor 4 (ATF4) resulted in the induction of HSPA5, which in identify a novel role of HSPA5 in ferroptosis and suggest a turn bound glutathione peroxidase 4 (GPX4) and protected potential therapeutic strategy for overcoming gemcitabine against GPX4 protein degradation and subsequent lipid per- resistance. Cancer Res; 77(8); 2064–77. Ó2017 AACR. Introduction contributes to ferroptotic cancer death (4). Conditional knockout of GPX4 in mice enhances ferroptosis in vivo (5–7). In addition to The therapeutic goal of all cancer treatment has been to trigger inhibition of GPX4 activity, increased GPX4 degradation also tumor-selective cell death and spare normal tissues. Acquisition of contributes to ferroptotic cancer cell death (8, 9). various genetic or epigenetic alterations in cancer cells may result The heatshock 70 kDa protein 5 (HSPA5, also termed GRP78 or in drug resistance by activating stress-adaptation responses such BIP) is a member of the molecular chaperones expressed primarily as the heat shock response or the unfolded protein response.
    [Show full text]
  • Ferroptosis: Past, Present and Future Jie Li 1,2,Fengcao3, He-Liang Yin4,5, Zi-Jian Huang1,2, Zhi-Tao Lin1,2,Ningmao1,2,Beisun1,2 and Gang Wang1,2
    Li et al. Cell Death and Disease (2020) 11:88 https://doi.org/10.1038/s41419-020-2298-2 Cell Death & Disease REVIEW ARTICLE Open Access Ferroptosis: past, present and future Jie Li 1,2,FengCao3, He-liang Yin4,5, Zi-jian Huang1,2, Zhi-tao Lin1,2,NingMao1,2,BeiSun1,2 and Gang Wang1,2 Abstract Ferroptosis is a new type of cell death that was discovered in recent years and is usually accompanied by a large amount of iron accumulation and lipid peroxidation during the cell death process; the occurrence of ferroptosis is iron-dependent. Ferroptosis-inducing factors can directly or indirectly affect glutathione peroxidase through different pathways, resulting in a decrease in antioxidant capacity and accumulation of lipid reactive oxygen species (ROS) in cells, ultimately leading to oxidative cell death. Recent studies have shown that ferroptosis is closely related to the pathophysiological processes of many diseases, such as tumors, nervous system diseases, ischemia-reperfusion injury, kidney injury, and blood diseases. How to intervene in the occurrence and development of related diseases by regulating cell ferroptosis has become a hotspot and focus of etiological research and treatment, but the functional changes and specific molecular mechanisms of ferroptosis still need to be further explored. This paper systematically summarizes the latest progress in ferroptosis research, with a focus on providing references for further understanding of its pathogenesis and for proposing new targets for the treatment of related diseases. Facts peroxides, or can other substances take the place of iron in ferroptosis? What is the downstream regulation mechanism of iron 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Ferroptosis is a new type of programmed cell death, in ferroptosis? which occurs with iron dependence.
    [Show full text]
  • Cell Ferroptosis: New Mechanism and New Hope for Retinitis Pigmentosa
    cells Review Cell Ferroptosis: New Mechanism and New Hope for Retinitis Pigmentosa Ming Yang 1 , Kwok-Fai So 1,2,3, Wai-Ching Lam 1,* and Amy Cheuk Yin Lo 1,* 1 Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China; [email protected] (M.Y.); [email protected] (K.-F.S.) 2 State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong 999077, China 3 GHM Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China * Correspondence: [email protected] (W.-C.L.); [email protected] (A.C.Y.L.) Abstract: Retinitis pigmentosa (RP) is a leading cause of inherited retinal degeneration, with more than 60 gene mutations. Despite the genetic heterogenicity, photoreceptor cell damage remains the hallmark of RP pathology. As a result, RP patients usually suffer from reduced night vision, loss of peripheral vision, decreased visual acuity, and impaired color perception. Although photoreceptor cell death is the primary outcome of RP, the underlying mechanisms are not completely elucidated. Ferroptosis is a novel programmed cell death, with characteristic iron overload and lipid peroxidation. Recent studies, using in vitro and in vivo RP models, discovered the involvement of ferroptosis- associated cell death, suggesting a possible new mechanism for RP pathogenesis. In this review, we discuss the association between ferroptosis and photoreceptor cell damage, and its implication in the pathogenesis of RP. We propose that ferroptotic cell death not only opens up a new research area in RP, but may also serve as a novel therapeutic target for RP.
    [Show full text]