Abstract
Ferroptosis is an iron-dependent form of non-apoptotic cell death, but its molecular mechanism remains largely unknown. Here, we demonstrate that heat shock protein beta-1 (HSPB1) is a negative regulator of ferroptotic cancer cell death. Erastin, a specific ferroptosis-inducing compound, stimulates heat shock factor 1 (HSF1)-dependent HSPB1 expression in cancer cells. Knockdown of HSF1 and HSPB1 enhances erastin-induced ferroptosis, whereas heat shock pretreatment and overexpression of HSPB1 inhibits erastin-induced ferroptosis. Protein kinase C-mediated HSPB1 phosphorylation confers protection against ferroptosis by reducing iron-mediated production of lipid reactive oxygen species. Moreover, inhibition of the HSF1–HSPB1 pathway and HSPB1 phosphorylation increases the anticancer activity of erastin in human xenograft mouse tumor models. Our findings reveal an essential role for HSPB1 in iron metabolism with important effects on ferroptosis-mediated cancer therapy.
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References
Galluzzi L, Vitale I, Abrams JM, Alnemri ES, Baehrecke EH, Blagosklonny MV et al. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ 2012; 19: 107–120.
Galluzzi L, Bravo-San Pedro JM, Vitale I, Aaronson SA, Abrams JM, Adam D et al. Essential versus accessory aspects of cell death: recommendations of the NCCD 2015. Cell Death Differ 2014; 22: 58–73.
Fuchs Y, Steller H . Programmed cell death in animal development and disease. Cell 2011; 147: 742–758.
Vanden Berghe T, Linkermann A, Jouan-Lanhouet S, Walczak H, Vandenabeele P . Regulated necrosis: the expanding network of non-apoptotic cell death pathways. Nat Rev Mol Cell Biol 2014; 15: 135–147.
Tait SW, Ichim G, Green DR . Die another way—non-apoptotic mechanisms of cell death. J Cell Sci 2014; 127: 2135–2144.
Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 2012; 149: 1060–1072.
Dixon SJ, Patel DN, Welsch M, Skouta R, Lee ED, Hayano M et al. Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. Elife 2014; 3: e02523.
Dolma S, Lessnick SL, Hahn WC, Stockwell BR . Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell 2003; 3: 285–296.
Yagoda N, von Rechenberg M, Zaganjor E, Bauer AJ, Yang WS, Fridman DJ et al. RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature 2007; 447: 864–868.
Yang WS, Stockwell BR . Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem Biol 2008; 15: 234–245.
Dixon SJ, Stockwell BR . The role of iron and reactive oxygen species in cell death. Nat Chem Biol 2014; 10: 9–17.
Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS et al. Regulation of ferroptotic cancer cell death by GPX4. Cell 2014; 156: 317–331.
Friedmann Angeli JP, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol 2014; 16: 1180–1191.
Linkermann A, Skouta R, Himmerkus N, Mulay SR, Dewitz C, De Zen F et al. Synchronized renal tubular cell death involves ferroptosis. Proc Natl Acad Sci USA 2014; 111: 16836–16841.
Georgopoulos C, Welch WJ . Role of the major heat shock proteins as molecular chaperones. Annu Rev Cell Biol 1993; 9: 601–634.
Wu C . Heat shock transcription factors: structure and regulation. Annu Rev Cell Dev Biol 1995; 11: 441–469.
Takayama S, Reed JC, Homma S . Heat-shock proteins as regulators of apoptosis. Oncogene 2003; 22: 9041–9047.
Ramanathan R, Mancini RA, Suman SP, Beach CM . Covalent binding of 4-hydroxy-2-nonenal to lactate dehydrogenase decreases NADH formation and metmyoglobin reducing activity. J Agric Food Chem 2014; 62: 2112–2117.
Guettouche T, Boellmann F, Lane WS, Voellmy R . Analysis of phosphorylation of human heat shock factor 1 in cells experiencing a stress. BMC Biochem 2005; 6: 4.
Xu L, Chen S, Bergan RC . APKAPK2 and HSP27 are downstream effectors of p38 MAP kinase-mediated matrix metalloproteinase type 2 activation and cell invasion in human prostate cancer. Oncogene 2006; 25: 2987–2998.
Lavoie JN, Hickey E, Weber LA, Landry J . Modulation of actin microfilament dynamics and fluid phase pinocytosis by phosphorylation of heat shock protein 27. J Biol Chem 1993; 268: 24210–24214.
Rousseau S, Houle F, Landry J, Huot J . p38 MAP kinase activation by vascular endothelial growth factor mediates actin reorganization and cell migration in human endothelial cells. Oncogene 1997; 15: 2169–2177.
Takenawa T, Suetsugu S . The WASP-WAVE protein network: connecting the membrane to the cytoskeleton. Nat Rev Mol Cell Biol 2007; 8: 37–48.
Shin KD, Lee MY, Shin DS, Lee S, Son KH, Koh S et al. Blocking tumor cell migration and invasion with biphenyl isoxazole derivative KRIBB3, a synthetic molecule that inhibits Hsp27 phosphorylation. J Biol Chem 2005; 280: 41439–41448.
Fulda S, Gorman AM, Hori O, Samali A . Cellular stress responses: cell survival and cell death. Int J Cell Biol 2010; 2010: 214074.
Zhang Q, Kang R, Zeh HJ 3rd, Lotze MT, Tang D . DAMPs and autophagy: cellular adaptation to injury and unscheduled cell death. Autophagy 2013; 9: 451–458.
Carver JA, Rekas A, Thorn DC, Wilson MR . Small heat-shock proteins and clusterin: intra- and extracellular molecular chaperones with a common mechanism of action and function? IUBMB Life 2003; 55: 661–668.
Jakob U, Gaestel M, Engel K, Buchner J . Small heat shock proteins are molecular chaperones. J Biol Chem 1993; 268: 1517–1520.
Huot J, Houle F, Spitz DR, Landry J . HSP27 phosphorylation-mediated resistance against actin fragmentation and cell death induced by oxidative stress. Cancer Res 1996; 56: 273–279.
Tang D, Kang R, Livesey KM, Kroemer G, Billiar TR, Van Houten B et al. High-mobility group box 1 is essential for mitochondrial quality control. Cell Metab 2011; 13: 701–711.
Guay J, Lambert H, Gingras-Breton G, Lavoie JN, Huot J, Landry J . Regulation of actin filament dynamics by p38 map kinase-mediated phosphorylation of heat shock protein 27. J Cell Sci 1997; 110: 357–368.
Butt E, Immler D, Meyer HE, Kotlyarov A, Laass K, Gaestel M . Heat shock protein 27 is a substrate of cGMP-dependent protein kinase in intact human platelets: phosphorylation-induced actin polymerization caused by HSP27 mutants. J Biol Chem 2001; 276: 7108–7113.
Hentze MW, Muckenthaler MU, Galy B, Camaschella C . Two to tango: regulation of Mammalian iron metabolism. Cell 2010; 142: 24–38.
Chen H, Zheng C, Zhang Y, Chang YZ, Qian ZM, Shen X . Heat shock protein 27 downregulates the transferrin receptor 1-mediated iron uptake. Int J Biochem Cell Biol 2006; 38: 1402–1416.
Arrigo AP, Virot S, Chaufour S, Firdaus W, Kretz-Remy C, Diaz-Latoud C . Hsp27 consolidates intracellular redox homeostasis by upholding glutathione in its reduced form and by decreasing iron intracellular levels. Antioxid Redox Signal 2005; 7: 414–422.
Zhang X, Min X, Li C, Benjamin IJ, Qian B, Ding Z et al. Involvement of reductive stress in the cardiomyopathy in transgenic mice with cardiac-specific overexpression of heat shock protein 27. Hypertension 2010; 55: 1412–1417.
Torti SV, Torti FM . Iron and cancer: more ore to be mined. Nat Rev Cancer 2013; 13: 342–355.
Oesterreich S, Weng CN, Qiu M, Hilsenbeck SG, Osborne CK, Fuqua SA . The small heat shock protein hsp27 is correlated with growth and drug resistance in human breast cancer cell lines. Cancer Res 1993; 53: 4443–4448.
Skouta R, Dixon SJ, Wang J, Dunn DE, Orman M, Shimada K et al. Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models. J Am Chem Soc 2014; 136: 4551–4556.
Vidyasagar A, Wilson NA, Djamali A . Heat shock protein 27 (HSP27): biomarker of disease and therapeutic target. Fibrogenesis Tissue Repair 2012; 5: 7.
Lee YJ, Lee DH, Cho CK, Bae S, Jhon GJ, Lee SJ et al. HSP25 inhibits protein kinase C delta-mediated cell death through direct interaction. J Biol Chem 2005; 280: 18108–18119.
Huang J, Ni J, Liu K, Yu Y, Xie M, Kang R et al. HMGB1 promotes drug resistance in osteosarcoma. Cancer Res 2012; 72: 230–238.
Livesey KM, Kang R, Vernon P, Buchser W, Loughran P, Watkins SC et al. p53/HMGB1 complexes regulate autophagy and apoptosis. Cancer Res 2012; 72: 1996–2005.
Tang D, Shi Y, Jang L, Wang K, Xiao W, Xiao X . Heat shock response inhibits release of high mobility group box 1 protein induced by endotoxin in murine macrophages. Shock 2005; 23: 434–440.
Yang L, Xie M, Yang M, Yu Y, Zhu S, Hou W et al. PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis. Nat Commun 2014; 5: 4436.
Acknowledgements
We thank Christine Heiner (Department of Surgery, University of Pittsburgh) for her critical reading of the manuscript. This work was supported by the National Institutes of Health (R01CA160417 to DT), a 2013 Pancreatic Cancer Action Network-AACR Career Development Award (Grant Number 13-20-25-TANG), The National Natural Science Foundation-Guangdong Joint Fund (U1132005 to XS) and Science and Information Technology of Guangzhou Key Project (2011Y1-00038 to XS). HW is supported by grants from the National Center of Complementary and Alternative Medicine (R01AT005076) and the National Institute of General Medical Sciences (R01GM063075).
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Sun, X., Ou, Z., Xie, M. et al. HSPB1 as a novel regulator of ferroptotic cancer cell death. Oncogene 34, 5617–5625 (2015). https://doi.org/10.1038/onc.2015.32
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DOI: https://doi.org/10.1038/onc.2015.32
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