肾癌中调节性细胞死亡的新动向和未来展望

doi:10.19401/j.cnki.1007-3639.2022.10.008

摘要/Abstract

摘要：

肾癌是泌尿系统常见的恶性肿瘤之一。近年来，我国肾癌的发病率呈逐年上升的趋势，严重威胁着人们的健康。调节性细胞死亡是由一种细胞主动有序的死亡方式，普遍存在于生命活动过程中，在维系生命活动的平衡中发挥着至关重要的作用。近期Science杂志上报道了一种新的调节性细胞死亡方式即铜死亡，进一步强化了生命体中细胞死亡的重要性。随着对调节性细胞死亡认识的不断深入，越来越多的研究显示不同的调节性细胞死亡（如铁死亡、焦亡、自噬等）均与肾癌的发生、发展密切相关。如诱导细胞铁死亡将显著抑制肾癌的侵袭和转移、并与肾癌患者的更好预后密切相关；细胞焦亡不仅可以诱导肾癌细胞死亡还可以激活抗肾癌的免疫应答；自噬在肾癌中具有“双向”作用，增强自噬可抑制肾癌细胞生长，但也可能减弱联合用药治疗的效果；抑制细胞凋亡和坏死性凋亡可以显著促进肾癌细胞的增殖、侵袭等。本文将综述铁死亡、细胞焦亡、自噬、细胞凋亡和坏死性凋亡的分子机制和在肾癌发生、发展中作用的研究进展并进行展望，为探索肾癌的发病机制和潜在的治疗靶点提供新的视角。

关键词: 肾癌, 铜死亡, 铁死亡, 焦亡, 自噬, 坏死性凋亡, 细胞凋亡

Abstract:

Renal cell carcinoma is one of the most common malignancies in genitourinary cancers. In China, the incidence of renal cell carcinoma has been increasing year by year. Regulated cell death is a cell-independent and orderly death controlled by genes, which is ubiquitous in organisms and plays a crucial role in maintaining the cell homeostasis. Recently, cuproptosis was reported in Science, which further reinforced the importance of cell death in living organisms. With the increasing understanding of regulated cell death, more and more studies have shown that regulated cell death (such as ferroptosis, autophagy, pyroptosis) is closely related to the tumorigenesis and development of renal cell carcinoma. For example, induction of ferroptosis inhibits the invasion and metastasis of renal cell carcinoma and is closely related with better prognosis; pyroptosis not only induce renal cancer cell death and also activate the immune-response against renal cancer; autophagy plays a "bidirectional" role in renal cell carcinoma, which can inhibit the growth of renal cell carcinoma cells but may weaken the efficacy of combinational therapy; inhibition of apoptosis and necrotizing apoptosis can significantly promote the proliferation and invasion of renal cell carcinoma. This review has summarized the molecular mechanisms of ferroptosis, pyroptosis, autophagy, apoptosis and necrotizing apoptosis and the advances of different regulatory cell death in the tumorigenesis and development of renal cell carcinoma to provide a new perspective for exploring the mechanisms of tumorigenesis and potential targets of treatment.

Key words: Renal cell carcinoma, Cuproptosis, Ferroptosis, Autophagy, Pyroptosis, Necroptosis, Apoptosis

中图分类号:

R737.11

曹达龙综述, 叶定伟审校. 肾癌中调节性细胞死亡的新动向和未来展望[J]. 中国癌症杂志, 2022, 32(10): 1000-1006.

CAO Dalong, YE Dingwei. New trends and future prospects of regulatory cell death in renal carcinoma[J]. China Oncology, 2022, 32(10): 1000-1006.

参考文献 51

[1]	SUNG H, FERLAY J, SIEGEL R L, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA A Cancer J Clin, 2021, 71(3): 209-249. doi: 10.3322/caac.21660
[2]	BRAY F, FERLAY J, SOERJOMATARAM I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA A Cancer J Clin, 2018, 68(6): 394-424. doi: 10.3322/caac.21492
[3]	ZHENG R S, ZHANG S W, ZENG H M, et al. Cancer incidence and mortality in China, 2016[J]. J Natl Cancer Cent, 2022, 2(1): 1-9.
[4]	CHEN W Q, ZHENG R S, BAADE P D, et al. Cancer statistics in China, 2015[J]. CA Cancer J Clin, 2016, 66(2): 115-132. doi: 10.3322/caac.21338
[5]	COHEN H T, MCGOVERN F J. Renal-cell carcinoma[J]. N Engl J Med, 2005, 353(23): 2477-2490. doi: 10.1056/NEJMra043172
[6]	POWLES T, PLIMACK E R, SOULIÈRES D, et al. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial[J]. Lancet Oncol, 2020, 21(12): 1563-1573. doi: 10.1016/S1470-2045(20)30436-8 pmid: 33284113
[7]	MOTZER R J, TANNIR N M, MCDERMOTT D F, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma[J]. N Engl J Med, 2018, 378(14): 1277-1290. doi: 10.1056/NEJMoa1712126
[8]	FUCHS Y, STELLER H. Programmed cell death in animal development and disease[J]. Cell, 2011, 147(4): 742-758. doi: 10.1016/j.cell.2011.10.033 pmid: 22078876
[9]	TSVETKOV P, COY S, PETROVA B, et al. Copper induces cell death by targeting lipoylated TCA cycle proteins[J]. Science, 2022, 375(6586): 1254-1261. doi: 10.1126/science.abf0529 pmid: 35298263
[10]	LI J, CAO F, YIN H L, et al. Ferroptosis: past, present and future[J]. Cell Death Dis, 2020, 11(2): 88. doi: 10.1038/s41419-020-2298-2 pmid: 32015325
[11]	FANG Y, TIAN S W, PAN Y T, et al. Pyroptosis: a new frontier in cancer[J]. Biomedecine Pharmacother, 2020, 121: 109595.
[12]	LEVY J M M, TOWERS C G, THORBURN A. Targeting autophagy in cancer[J]. Nat Rev Cancer, 2017, 17(9): 528-542. doi: 10.1038/nrc.2017.53 pmid: 28751651
[13]	CARNEIRO B A, EL-DEIRY W S. Targeting apoptosis in cancer therapy[J]. Nat Rev Clin Oncol, 2020, 17(7): 395-417. doi: 10.1038/s41571-020-0341-y pmid: 32203277
[14]	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. doi: 10.1016/j.cell.2012.03.042 pmid: 22632970
[15]	DOLMA S, LESSNICK S L, HAHN W C, et al. Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells[J]. Cancer Cell, 2003, 3(3): 285-296. pmid: 12676586
[16]	ZHOU B R, LIU J, KANG R, et al. Ferroptosis is a type of autophagy-dependent cell death[J]. Semin Cancer Biol, 2020, 66: 89-100. doi: S1044-579X(19)30006-9 pmid: 30880243
[17]	LEI G, ZHUANG L, GAN B Y. Targeting ferroptosis as a vulnerability in cancer[J]. Nat Rev Cancer, 2022, 22(7): 381-396. doi: 10.1038/s41568-022-00459-0 pmid: 35338310
[18]	YANG W S, SRIRAMARATNAM R, WELSCH M E, et al. Regulation of ferroptotic cancer cell death by GPX4[J]. Cell, 2014, 156(1/2): 317-331. doi: 10.1016/j.cell.2013.12.010
[19]	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. doi: 10.1038/s41388-018-0315-z pmid: 29872221
[20]	YANG W H, DING C K C, SUN T A, et al. The hippo pathway effector TAZ regulates ferroptosis in renal cell carcinoma[J]. Cell Rep, 2019, 28(10): 2501-2508.e4. doi: 10.1016/j.celrep.2019.07.107
[21]	LEE H, ZANDKARIMI F, ZHANG Y L, et al. Energy-stress-mediated AMPK activation inhibits ferroptosis[J]. Nat Cell Biol, 2020, 22(2): 225-234. doi: 10.1038/s41556-020-0461-8 pmid: 32029897
[22]	LU Y Q, QIN H X, JIANG B, et al. KLF2 inhibits cancer cell migration and invasion by regulating ferroptosis through GPX4 in clear cell renal cell carcinoma[J]. Cancer Lett, 2021, 522: 1-13. doi: 10.1016/j.canlet.2021.09.014 pmid: 34520818
[23]	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. doi: 10.1111/cas.13701
[24]	COOKSON B T, BRENNAN M A. Pro-inflammatory programmed cell death[J]. Trends Microbiol, 2001, 9(3): 113-114. pmid: 11303500
[25]	LIU X, ZHANG Z B, RUAN J B, et al. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores[J]. Nature, 2016, 535(7610): 153-158. doi: 10.1038/nature18629
[26]	SHI J J, GAO W Q, SHAO F. Pyroptosis: gasdermin-mediated programmed necrotic cell death[J]. Trends Biochem Sci, 2017, 42(4): 245-254. doi: S0968-0004(16)30182-7 pmid: 27932073
[27]	KAYAGAKI N, WONG M T, STOWE I B, et al. Noncanonical inflammasome activation by intracellular LPS independent of TLR4[J]. Science, 2013, 341(6151): 1246-1249. doi: 10.1126/science.1240248 pmid: 23887873
[28]	LAGRANGE B, BENAOUDIA S, WALLET P, et al. Human caspase-4 detects tetra-acylated LPS and cytosolic Francisella and functions differently from murine caspase-11[J]. Nat Commun, 2018, 9(1): 242. doi: 10.1038/s41467-017-02682-y pmid: 29339744
[29]	WANG Y P, GAO W Q, SHI X Y, et al. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin[J]. Nature, 2017, 547(7661): 99-103. doi: 10.1038/nature22393
[30]	HOU J W, ZHAO R C, XIA W Y, et al. PD-L1-mediated gasdermin C expression switches apoptosis to pyroptosis in cancer cells and facilitates tumour necrosis[J]. Nat Cell Biol, 2020, 22(10): 1264-1275. doi: 10.1038/s41556-020-0575-z pmid: 32929201
[31]	WEI X, XIE F, ZHOU X X, et al. Role of pyroptosis in inflammation and cancer[J]. Cell Mol Immunol, 2022, 19(9): 971-992. doi: 10.1038/s41423-022-00905-x pmid: 35970871
[32]	SUN Z L, JING C Y, GUO X D, et al. Comprehensive analysis of the immune infiltrates of pyroptosis in kidney renal clear cell carcinoma[J]. Front Oncol, 2021, 11: 716854. doi: 10.3389/fonc.2021.716854
[33]	YAO L, LI J N, XU Z J, et al. GSDMs are potential therapeutic targets and prognostic biomarkers in clear cell renal cell carcinoma[J]. Aging, 2022, 14(6): 2758-2774. doi: 10.18632/aging.203973
[34]	TANG X F, ZHANG A N, FENG Y Y, et al. A novel pyroptosis-related lncRNAs signature for predicting the prognosis of kidney renal clear cell carcinoma and its associations with immunity[J]. J Oncol, 2021, 2021: 9997185.
[35]	TAN Y F, WANG M, CHEN Z Y, et al. Inhibition of BRD4 prevents proliferation and epithelial-mesenchymal transition in renal cell carcinoma via NLRP3 inflammasome-induced pyroptosis[J]. Cell Death Dis, 2020, 11(4): 239. doi: 10.1038/s41419-020-2431-2
[36]	CHOI A M, RYTER S W, LEVINE B. Autophagy in human health and disease[J]. N Engl J Med, 2013, 368(7): 651-662. doi: 10.1056/NEJMra1205406
[37]	LEVINE B, KROEMER G. Biological functions of autophagy genes: a disease perspective[J]. Cell, 2019, 176(1/2): 11-42. doi: 10.1016/j.cell.2018.09.048
[38]	ALESSANDRINI F, PEZZÈ L, CIRIBILLI Y. LAMPs: shedding light on cancer biology[J]. Semin Oncol, 2017, 44(4): 239-253. doi: S0093-7754(17)30046-5 pmid: 29526252
[39]	ZHAO Y, CODOGNO P, ZHANG H. Machinery, regulation and pathophysiological implications of autophagosome maturation[J]. Nat Rev Mol Cell Biol, 2021, 22(11): 733-750. doi: 10.1038/s41580-021-00392-4
[40]	RUSSELL R C, GUAN K L. The multifaceted role of autophagy in cancer[J]. EMBO J, 2022, 41(13): e110031.
[41]	LEBOVITZ C B, ROBERTSON A G, GOYA R, et al. Cross-cancer profiling of molecular alterations within the human autophagy interaction network[J]. Autophagy, 2015, 11(9): 1668-1687. doi: 10.1080/15548627.2015.1067362 pmid: 26208877
[42]	KANG J H, LEE J S, HONG D, et al. Renal cell carcinoma escapes death by p53 depletion through transglutaminase 2-chaperoned autophagy[J]. Cell Death Dis, 2016, 7: e2163. doi: 10.1038/cddis.2016.14
[43]	TURCOTTE S, CHAN D A, SUTPHIN P D, et al. A molecule targeting VHL-deficient renal cell carcinoma that induces autophagy[J]. Cancer Cell, 2008, 14(1): 90-102. doi: 10.1016/j.ccr.2008.06.004 pmid: 18598947
[44]	YANG X Q, ZHANG Y Y, FAN H Y. Downregulation of SBF2-AS1 functions as a tumor suppressor in clear cell renal cell carcinoma by inhibiting miR-338-3p-targeted ETS1[J]. Cancer Gene Ther, 2021, 28(7/8): 813-827. doi: 10.1038/s41417-020-0197-4
[45]	LIANG X Y, DE VERA M E, BUCHSER W J, et al. Inhibiting systemic autophagy during interleukin 2 immunotherapy promotes long-term tumor regression[J]. Cancer Res, 2012, 72(11): 2791-2801. doi: 10.1158/0008-5472.CAN-12-0320 pmid: 22472122
[46]	PIETROCOLA F, POL J, VACCHELLI E, et al. Caloric restriction mimetics enhance anticancer immunosurveillance[J]. Cancer Cell, 2016, 30(1): 147-160. doi: S1535-6108(16)30221-5 pmid: 27411589
[47]	ZHANG T, WANG Y N, INUZUKA H, et al. Necroptosis pathways in tumorigenesis[J]. Semin Cancer Biol, 2022, 86(Pt 3): 32-40. doi: 10.1016/j.semcancer.2022.07.007
[48]	ZHAO C, ZHOU Y F, RAN Q, et al. microRNA-381-3p functions as a dual suppressor of apoptosis and necroptosis and promotes proliferation of renal cancer cells[J]. Front Cell Dev Biol, 2020, 8: 290. doi: 10.3389/fcell.2020.00290 pmid: 32411707
[49]	MAO Q Y, ZHUANG Q F, SHEN J, et al. MiRNA-124 regulates the sensitivity of renal cancer cells to cisplatin-induced necroptosis by targeting the CAPN4-CNOT3 axis[J]. Transl Androl Urol, 2021, 10(9): 3669-3683. doi: 10.21037/tau-21-777 pmid: 34733662
[50]	WANG K J, MENG X Y, CHEN J F, et al. Emodin induced necroptosis and inhibited glycolysis in the renal cancer cells by enhancing ROS[J]. Oxid Med Cell Longev, 2021, 2021: 8840590.
[51]	BRADLEY J R, WANG J, PACEY S, et al. Tumor necrosis factor receptor-2 signaling pathways promote survival of cancer stem-like CD133+ cells in clear cell renal carcinoma[J]. FASEB Bioadvances, 2020, 2(2): 126-144. doi: 10.1096/fba.2019-00071