Abstract
Ferroptosis is a newly characterized iron-dependent form of nonapoptotic regulated cell death triggered by lipid reactive oxygen species (LOOH). The dysregulation of ferroptosis is highly related to cancer, and the induction of ferroptosis is also proposed as a potential strategy for cancer therapy. Although several key regulators have been identified that are involved in ferroptosis, the molecular mechanism underlying this process remains largely unknown. Here, we report that Peroxiredoxin-6 (PRDX6) is a bona fide negative regulator of ferroptotic cell death. The knockdown of intracellular PRDX6 significantly enhances LOOH and ferroptotic cell death triggered by ferroptosis inducers (Erastin and RSL-3), which is correlated with the transcriptional activation of heme oxygenase-1. Moreover, overexpression of heme oxygenase-1 enhances both Erastin- and RSL-3-triggered LOOH, suggesting that heme oxygenase-1 mediates PRDX6 silencing-enhanced ferroptosis. More importantly, the application of a specific PRDX6 phospholipase A2 (iPLA2) inhibitor, MJ-33, synergistically enhances the ferroptosis induced by Erastin, suggesting that PRDX6 removes LOOH through its iPLA2 activity. Thus, our findings reveal an essential role of PRDX6 in protecting cells against ferroptosis and provide a potential target to improve the antitumor activity of ferroptosis-based chemotherapy.
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References
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;149:1060–72.
Yang WS, Kim KJ, Gaschler MM, Patel M, Shchepinov MS, Stockwell BR. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc Natl Acad Sci USA. 2016;113:E4966–75.
Doll S, Proneth B, Tyurina YY, Panzilius E, Kobayashi S, Ingold I, et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 2017;13:91–8.
Kagan VE, Mao G, Qu F, Angeli JP, Doll S, Croix CS, et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol. 2017;13:81–90.
Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 2017;171:273–85.
Lu B, Chen XB, Ying MD, He QJ, Cao J, Yang B. The role of ferroptosis in cancer development and treatment response. Front Pharmacol. 2017;8:992.
Yang WS, Stockwell BR. Ferroptosis: death by lipid peroxidation. Trends Cell Biol. 2016;26:165–76.
Xie Y, Hou W, Song X, Yu Y, Huang J, Sun X, et al. Ferroptosis: process and function. Cell Death Differ. 2016;23:369–79.
Jiang L, Kon N, Li T, Wang SJ, Su T, Hibshoosh H, et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature. 2015;520:57–62.
Xie Y, Zhu S, Song X, Sun X, Fan Y, Liu J, et al. The tumor suppressor p53 limits ferroptosis by blocking DPP4 activity. Cell Rep. 2017;20:1692–704.
Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014;156:317–31.
Roh JL, Kim EH, Jang HJ, Park JY, Shin D. Induction of ferroptotic cell death for overcoming cisplatin resistance of head and neck cancer. Cancer Lett. 2016;381:96–103.
Yu Y, Xie Y, Cao L, Yang L, Yang M, Lotze MT, et al. The ferroptosis inducer Erastin enhances sensitivity of acute myeloid leukemia cells to chemotherapeutic agents. Mol Cell Oncol. 2015;2:e1054549.
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;16:1180–91.
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.
Sun X, Ou Z, Xie M, Kang R, Fan Y, Niu X, et al. HSPB1 as a novel regulator of ferroptotic cancer cell death. Oncogene. 2015;34:5617–25.
Sun X, Ou Z, Chen R, Niu X, Chen D, Kang R, et al. Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology. 2016;63:173–84.
Dixon SJ, Winter GE, Musavi LS, Lee ED, Snijder B, Rebsamen M, et al. Human haploid cell genetics reveals roles for lipid metabolism genes in nonapoptotic cell death. ACS Chem Biol. 2015;10:1604–9.
Rhee SG, Chae HZ, Kim K. Peroxiredoxins: a historical overview and speculative preview of novel mechanisms and emerging concepts in cell signaling. Free Radic Biol Med. 2005;38:1543–52.
Rhee SG, Kang SW, Chang TS, Jeong W, Kim K. Peroxiredoxin, a novel family of peroxidases. IUBMB Life. 2001;52:35–41.
Fisher AB, Vasquez-Medina JP, Dodia C, Sorokina EM, Tao JQ, Feinstein SI. Peroxiredoxin 6 phospholipid hydroperoxidase activity in the repair of peroxidized cell membranes. Redox Biol. 2018;14:41–6.
Fisher AB. Peroxiredoxin 6 in the repair of peroxidized cell membranes and cell signaling. Arch Biochem Biophys. 2017;617:68–83.
Fisher AB, Dodia C, Sorokina EM, Li H, Zhou S, Raabe T, et al. A novel lysophosphatidylcholine acyl transferase activity is expressed by peroxiredoxin 6. J Lipid Res. 2016;57:587–96.
Xu Z, Jin Y, Yan H, Gao Z, Xu B, Yang B, et al. High-mobility group box 1 protein-mediated necroptosis contributes to dasatinib-induced cardiotoxicity. Toxicol Lett. 2018;296:39–47.
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;3:285–96.
Yang WS, Stockwell BR. Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem Biol. 2008;15:234–45.
Zilka O, Shah R, Li B, Friedmann Angeli JP, Griesser M, Conrad M, et al. On the mechanism of cytoprotection by ferrostatin-1 and liproxstatin-1 and the role of lipid peroxidation in ferroptotic cell death. ACS Cent Sci. 2017;3:232–43.
Chowdhury I, Mo Y, Gao L, Kazi A, Fisher AB, Feinstein SI. Oxidant stress stimulates expression of the human peroxiredoxin 6 gene by a transcriptional mechanism involving an antioxidant response element. Free Radic Biol Med. 2009;46:146–53.
Kansanen E, Kuosmanen SM, Leinonen H, Levonen AL. The Keap1-Nrf2 pathway: mechanisms of activation and dysregulation in cancer. Redox Biol. 2013;1:45–9.
Kwon MY, Park E, Lee SJ, Chung SW. Heme oxygenase-1 accelerates Erastin-induced ferroptotic cell death. Oncotarget. 2015;6:24393–403.
Lanceta L1, Li C, Choi AM, Eaton JW. Haem oxygenase-1 overexpression alters intracellular iron distribution. Biochem J. 2013;449:189–94.
Chen JW, Dodia C, Feinstein SI, Jain MK, Fisher AB. 1-Cys peroxiredoxin, a bifunctional enzyme with glutathione peroxidase and phospholipase A2 activities. J Biol Chem. 2000;275:28421–7.
Fatma N, Kubo E, Sharma P, Beier DR, Singh DP. Impaired homeostasis and phenotypic abnormalities in Prdx6-/-mice lens epithelial cells by reactive oxygen species: increased expression and activation of TGFbeta. Cell Death Differ. 2005;12:734–50.
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;136:4551–6.
Lee DH, Park JH, Han SB, Yoon DY, Jung YY, Hong JT. Peroxiredoxin 6 overexpression attenuates lipopolysaccharide-induced acute kidney injury. Oncotarget. 2017;8:51096–107.
Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (No. 81872885 to Ji Cao; No. 81625024 to Bo Yang), the Department of Education of Zhejiang Province (Y201430401 to Ji Cao), the Talent Project of Zhejiang Association for Science and Technology (No. 2018YCGC002 to Ji Cao) and the Project of Zhejiang Medical Science and Technology (2015KYA141 to Yu-cai Hong). We thank Dr. Nicole Spiegelman and Dr. Zhen Tong for language editing.
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JC, MDY, BY, QJH, and BL designed the research project; BL and XBC performed the experiments; JC and BL analyzed the data; HZ and YCH contributed the reagents; JC, BL, and XBC wrote the paper.
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Lu, B., Chen, Xb., Hong, Yc. et al. Identification of PRDX6 as a regulator of ferroptosis. Acta Pharmacol Sin 40, 1334–1342 (2019). https://doi.org/10.1038/s41401-019-0233-9
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DOI: https://doi.org/10.1038/s41401-019-0233-9
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