铁死亡信号介导抗肿瘤作用的细胞器调控机制研究进展

doi:10.3969/j.issn.1004-616x.2020.02.012

摘要/Abstract

摘要： 铁死亡是一种非凋亡性调节性细胞死亡（RCD），表现为多细胞器调节信号的变化。目前，已明确部分铁死亡上游执行机制，即不稳定铁池的产生和/或谷胱甘肽过氧化物酶4（GPX4）的抑制或失活，和下游的脂质过氧化物产生和积累的触发机制；同时铁死亡相关信号分子可发生蛋白质翻译后修饰参与信号网络功能调控。功能上，铁死亡既参与外源物诱导的致癌作用，也可介导外源物对肿瘤细胞的选择性杀伤作用。本综述拟阐述铁死亡的相关信号通路，阐明不同细胞器参与铁死亡调控的分子机制，探讨外源化学物靶向铁死亡信号分子介导的抗肿瘤作用，为铁死亡依赖性致癌作用防制策略提供新的理论依据。

关键词: 铁死亡, 信号通路调控, 线粒体, 内质网, 溶酶体, 细胞核, 肿瘤化学预防

中图分类号:

R730.1

郭倪君, 林忠宁, 林育纯. 铁死亡信号介导抗肿瘤作用的细胞器调控机制研究进展[J]. 癌变·畸变·突变, 2020, 32(2): 149-154.

参考文献

[1] DIXON S J, LEMBERG K M, LAMPRECHT M R, et al. Ferroptosis:an iron-dependent form of nonapoptotic cell death[J]. Cell, 2012, 149(5):1060-1072.
[2] YU M Y, GAI C C, LI Z, et al. Targeted exosome-encapsulated erastin induced ferroptosis in triple negative breast cancer cells[J]. Cancer Sci, 2019, 110(10):3173-3182.
[3] ZHOU B R, LIU J, KANG R, et al. Ferroptosis is a type of autophagy-dependent cell death[J]. Semin Cancer Biol, 2019:S1044-S579X(19)30006-9.
[4] WU Z M, GENG Y, LU X J, et al. Chaperone-mediated autophagy is involved in the execution of ferroptosis[J]. Proc Natl Acad Sci USA, 2019, 116(8):2996-3005.
[5] TANG D L, KANG R, BERGHE T V, et al. The molecular machinery of regulated cell death[J]. Cell Res, 2019, 29(5):347-364.
[6] KROEMER G, JÄÄTTELÄ M. Lysosomes and autophagy in cell death control[J]. Nat Rev Cancer, 2005, 5(11):886-897.
[7] SUN L M, WANG H Y, WANG Z G, et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase[J]. Cell, 2012, 148(1/2):213-227.
[8] PARISI L R, MORROW L M, VISSER M B, et al. Turning the spotlight on lipids in non-apoptotic cell death[J]. ACS Chem Biol, 2018, 13(3):506-515.
[9] FENG H Z, STOCKWELL B R. Unsolved mysteries:How does lipid peroxidation cause ferroptosis?[J]. PLoS Biol, 2018, 16(5):e2006203.
[10] BASULI D, TESFAY L, DENG Z, et al. Iron addiction:a novel therapeutic target in ovarian cancer[J]. Oncogene, 2017, 36(29):4089-4099.
[11] YANG W S, KIM K J, GASCHLER M M, et al. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis[J]. Proc Natl Acad Sci USA, 2016, 113(34):E4966-E4975.
[12] CHEN D, FAN Z, RAUH M, et al. ATF4 promotes angiogenesis and neuronal cell death and confers ferroptosis in a xCT-dependent manner[J]. Oncogene, 2017, 36(40):5593-5608.
[13] MIESS H, DANKWORTH B, GOUW A M, et al. The glutathione redox system is essential to prevent ferroptosis caused by impaired lipid metabolism in clear cell renal cell carcinoma[J]. Oncogene, 2018, 37(40):5435-5450.
[14] WANG W M, GREEN M, CHOI J E, et al. CD8⁺ T cells regulate tumour ferroptosis during cancer immunotherapy[J]. Nature, 2019, 569(7755):270-274.
[15] WU J, MINIKES A M, GAO M H, et al. Intercellular interaction dictates cancer cell ferroptosis via NF2-YAP signalling[J]. Nature, 2019, 572(7769):402-406.
[16] SUN X, OU Z, XIE M, et al. HSPB1 as a novel regulator of ferroptotic cancer cell death[J]. Oncogene, 2015, 34(45):5617-5625.
[17] SONG X X, ZHU S, CHEN P, et al. AMPK-mediated BECN1 phosphorylation promotes ferroptosis by directly blocking system xc-activity[J]. Curr Biol, 2018, 28(15):2388-2399.e5.
[18] CHEN Y, LIU Y, LAN T, et al. Quantitative profiling of protein carbonylations in ferroptosis by an aniline-derived probe[J]. J Am Chem Soc, 2018, 140(13):4712-4720.
[19] KERINS M J, MILLIGAN J, WOHLSCHLEGEL J A, et al. Fumarate hydratase inactivation in hereditary leiomyomatosis and renal cell cancer is synthetic lethal with ferroptosis induction[J]. Cancer Sci, 2018, 109(9):2757-2766.
[20] WANG S J, LI D W, OU Y, et al. Acetylation is crucial for p53-mediated ferroptosis and tumor suppression[J]. Cell Rep, 2016, 17(2):366-373.
[21] GALLUZZI L, KEPP O, KROEMER G. Mitochondrial regulation of cell death:a phylogenetically conserved control[J]. Microb Cell, 2016, 3(3):101-108.
[22] KRAINZ T, GASCHLER M M, LIM C, et al. A mitochondrial-targeted nitroxide is a potent inhibitor of ferroptosis[J]. ACS Cent Sci, 2016, 2(9):653-659.
[23] YUAN H, LI X M, ZHANG X Y, et al. CISD1 inhibits ferroptosis by protection against mitochondrial lipid peroxidation[J]. Biochem Biophys Res Commun, 2016, 478(2):838-844.
[24] GAO M H, YI J M, ZHU J J, et al. Role of mitochondria in ferroptosis[J]. Mol Cell, 2019, 73(2):354-363.e3.
[25] LEE Y S, LEE D H, CHOUDRY H A, et al. Ferroptosis-induced endoplasmic reticulum stress:crosstalk between ferroptosis and apoptosis[J]. Mol Cancer Res, 2018, 16(7):1073-1076.
[26] DIXON S J, PATEL D N, WELSCH M, et al. Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic Reticulum stress and ferroptosis[J]. Elife, 2014, 3:e02523.
[27] KAGAN V E, MAO G W, QU F, et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis[J]. Nat Chem Biol, 2017, 13(1):81-90.
[28] SETTEMBRE C, FRALDI A, MEDINA D L, et al. Signals from the lysosome:a control centre for cellular clearance and energy metabolism[J]. Nat Rev Mol Cell Biol, 2013, 14(5):283-296.
[29] MANCIAS J D, WANG X X, GYGI S P, et al. Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy[J]. Nature, 2014, 509(7498):105-109.
[30] TORⅡ S, SHINTOKU R, KUBOTA C, et al. An essential role for functional lysosomes in ferroptosis of cancer cells[J]. Biochem J, 2016, 473(6):769-777.
[31] YANG M H, CHEN P, LIU J, et al. Clockophagy is a novel selective autophagy process favoring ferroptosis[J]. Sci Adv, 2019, 5(7):eaaw2238.
[32] INGOLD I, BERNDT C, SCHMITT S, et al. Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis[J]. Cell, 2018, 172(3):409-422.e21.
[33] JIANG L, KON N, LI T Y, et al. Ferroptosis as a p53-mediated activity during tumour suppression[J]. Nature, 2015, 520(7545):57-62.
[34] XIE Y C, ZHU S, SONG X X, et al. The tumor suppressor p53 limits ferroptosis by blocking DPP4 activity[J]. Cell Rep, 2017, 20(7):1692-1704.
[35] MAO C, WANG X, LIU Y T, et al. A G3BP1-interacting lncRNA promotes ferroptosis and apoptosis in cancer via nuclear sequestration of p53[J]. Cancer Res, 2018, 78(13):3484-3496.
[36] SUN X F, NIU X H, CHEN R C, et al. Metallothionein-1G facilitates sorafenib resistance through inhibition of ferroptosis[J]. Hepatology, 2016, 64(2):488-500.
[37] ZHANG Y L, SHI J J, LIU X G, et al. BAP1 links metabolic regulation of ferroptosis to tumour suppression[J]. Nat Cell Biol, 2018, 20(10):1181-1192.
[38] LIN R Y, ZHANG Z H, CHEN L F, et al. Dihydroartemisinin (DHA) induces ferroptosis and causes cell cycle arrest in head and neck carcinoma cells[J]. Cancer Lett, 2016, 381(1):165-175.
[39] DU J, WANG T T, LI Y C, et al. DHA inhibits proliferation and induces ferroptosis of leukemia cells through autophagy dependent degradation of ferritin[J]. Free Radic Biol Med, 2019, 131:356-369.
[40] YAMAGUCHI Y, KASUKABE T, KUMAKURA S. Piperlongumine rapidly induces the death of human pancreatic cancer cells mainly through the induction of ferroptosis[J]. Int J Oncol, 2018, 52(3):1011-1022.
[41] WEI G F, SUN J H, HOU Z, et al. Novel antitumor compound optimized from natural saponin Albiziabioside A induced caspase-dependent apoptosis and ferroptosis as a p53 activator through the mitochondrial pathway[J]. Eur J Med Chem, 2018, 157:759-772.
[42] SHEN Z Y, LIU T, LI Y, et al. Fenton-reaction-acceleratable magnetic nanoparticles for ferroptosis therapy of orthotopic brain tumors[J]. ACS Nano, 2018, 12(11):11355-11365.
[43] ZHENG D W, LEI Q, ZHU J Y, et al. Switching apoptosis to ferroptosis:metal-organic network for high-efficiency anticancer therapy[J]. Nano Lett, 2017, 17(1):284-291.
[44] LIU T, LIU W L, ZHANG M K, et al. Ferrous-supply-regeneration nanoengineering for cancer-cell-specific ferroptosis in combination with imaging-guided photodynamic therapy[J]. ACS Nano, 2018, 12(12):12181-12192.
[45] WANG S F, LI F Y, QIAO R R, et al. Arginine-rich manganese silicate nanobubbles as a ferroptosis-inducing agent for tumor-targeted theranostics[J]. ACS Nano, 2018, 12(12):12380-12392.
[46] ZHANG F, LI F, LU G H, et al. Engineering magnetosomes for ferroptosis/immunomodulation synergism in cancer[J]. ACS Nano, 2019, 13(5):5662-5673.