p53信号通路调控铁死亡在肝细胞癌中的作用机制

李震; 刘江凯

doi:10.3969/j.issn.1001-5256.2023.04.032

p53信号通路调控铁死亡在肝细胞癌中的作用机制

DOI: 10.3969/j.issn.1001-5256.2023.04.032

李震¹,
刘江凯^2, , ,

1.
河南中医药大学第一临床医学院，郑州 450000
2.
河南中医药大学第一附属医院脾胃肝胆科，郑州 450000

基金项目:

国家自然科学基金(联合基金) (U1504825);

河南省高等学校重点科研项目 (20A360014);

河南省中医药拔尖人才培养项目资助 (Yuwei Chinese Medicine Letter [2021] No.15)

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：李震负责课题设计，资料收集，分析文献资料，撰写论文；刘江凯负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
刘江凯，xmlc001@126.com (ORCID: 0000-0002-1529-5089)

计量
- 文章访问数: 495
- HTML全文浏览量: 57
- PDF下载量: 49
- 被引次数: 0
出版历程
- 收稿日期: 2022-07-30
- 录用日期: 2022-08-31
- 出版日期: 2023-04-20

The mechanism of p53 signaling pathway regulating ferroptosis in hepatocellular carcinoma

Zhen LI¹,
Jiangkai LIU^{2
, ,
,}

1.
The First Clinical Medical College of Henan University of Chinese Medicine, Zhengzhou 450000, China
2.
Department of Hepatology and Spleen-Stomach, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, China

Research funding:

National Natural Science Foundation of China (Joint Fund) (U1504825);

Key Scientific Research Projects of Henan Province Colleges and Universities (20A360014);

Funded by Henan Province Traditional Chinese Medicine Top Talents Training Project (Yuwei Chinese Medicine Letter [2021] No.15)

More Information

Corresponding author: LIU Jiangkai, xmlc001@126.com (ORCID: 0000-0002-1529-5089)

摘要

摘要: 肝细胞癌(HCC)在我国是最常见的肝癌类型，其发生发展是一个复杂的病理过程。铁死亡作为一种新的细胞死亡方式，在治疗HCC方面有巨大的潜在作用。本文介绍了抑癌因子p53在调控铁死亡中的作用机制，简述其在HCC发生、发展中的作用。抑癌因子p53可以通过影响溶质载体家族7成员11、亚精胺/精胺N1-乙酰转移酶1、谷氨酰胺酶2、二肽基肽酶4和细胞周期蛋白依赖性激酶抑制剂1A来促进或抑制铁死亡，进而影响HCC的进展，通过调控铁死亡通路治疗HCC具有很大的应用前景。
- 铁死亡 /
- 癌，肝细胞 /
- 肿瘤抑制蛋白质p53
Abstract: Hepatocellular carcinoma (HCC) is the most common type of liver cancer in China, and the development and progression of HCC is a complex pathological process. As a new way of cell death, ferroptosis has huge potential in the treatment of HCC. This article introduces the mechanism of action of the tumor suppressor p53 in regulating ferroptosis and briefly describes its role in the development and progression of HCC. The tumor suppressor p53 can promote or inhibit ferroptosis by affecting solute carrier family 7 member 11, spermidine/spermine N1-acety-ltransferase 1, glutaminase 2, dipeptidyl peptidase 4, and cyclin-dependent kinase inhibitor 1A, which in turn affects the progression of HCC. The treatment of HCC by regulating the ferroptosis pathway has great application prospects.
- Ferroptosis /
- Carcinoma, Hepatocellular /
- Tumor Suppressor Protein p53

HTML全文

参考文献(35)

[1]	SUNG H, FERLAY J, SIEGEL RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249. DOI: 10.3322/caac.21660.
[2]	LI J, CAO F, YIN HL, et al. Ferroptosis: past, present and future[J]. Cell Death Dis, 2020, 11(2): 88. DOI: 10.1038/s41419-020-2298-2.
[3]	CAO JY, DIXON SJ. Mechanisms of ferroptosis[J]. Cell Mol Life Sci, 2016, 73(11-12): 2195-2209. DOI: 10.1007/s00018-016-2194-1.
[4]	CHEN C, JIANG JT. Mechanisms of ferroptosis and its applications in cancers[J]. Chin J Exp Surg, 2019, 36(11): 2110-2114. DOI: 10.3760/cma.j.issn.1001-9030.2019.11.058. 陈辰, 蒋敬庭. 铁死亡机制及在肿瘤中的应用进展[J]. 中华实验外科杂志, 2019, 36(11): 2110-2114. DOI: 10.3760/cma.j.issn.1001-9030.2019.11.058.
[5]	WANG HT, JU J, WANG SC, et al. Insights into ferroptosis, a novel target for the therapy of cancer[J]. Front Oncol, 2022, 12: 812534. DOI: 10.3389/fonc.2022.812534.
[6]	LIU M, KONG XY, YAO Y, et al. The critical role and molecular mechanisms of ferroptosis in antioxidant systems: a narrative review[J]. Ann Transl Med, 2022, 10(6): 368. DOI: 10.21037/atm-21-6942.
[7]	PAN F, LIN X, HAO L, et al. The critical role of ferroptosis in hepatocellular carcinoma[J]. Front Cell Dev Biol, 2022, 10: 882571. DOI: 10.3389/fcell.2022.882571.
[8]	LIEBL MC, HOFMANN TG. The role of p53 signaling in colorectal cancer[J]. Cancers (Basel), 2021, 13(9): 2125. DOI: 10.3390/cancers13092125.
[9]	LUO Q, BEAVER JM, LIU Y, et al. dynamics of p53: a master decider of cell fate[J]. Genes (Basel), 2017, 8(2): 66. DOI: 10.3390/genes8020066.
[10]	HARRIS CC. Structure and function of the p53 tumor suppressor gene: clues for rational cancer therapeutic strategies[J]. J Natl Cancer Inst, 1996, 88(20): 1442-1455. DOI: 10.1093/jnci/88.20.1442.
[11]	LIU J, ZHANG C, WANG J, et al. The regulation of ferroptosis by tumor suppress or p53 and its pathway[J]. Int J Mol Sci, 2020, 21(21): 8387. DOI: 10.3390/ijms21218387.
[12]	STEIN Y, ROTTER V, ALONI-GRINSTEIN R. Gain-of-function mutant p53: all the roads lead to tumorigenesis[J]. Int J Mol Sci, 2019, 20(24): 6197. DOI: 10.3390/ijms20246197.
[13]	KOPPULA P, ZHANG Y, ZHUANG L, et al. Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer[J]. Cancer Commun (Lond), 2018, 38(1): 12. DOI: 10.1186/s40880-018-0288-x.
[14]	JIANG L, KON N, LI T, et al. Ferroptosis as a p53-mediated activity during tumour suppression[J]. Nature, 2015, 520(7545): 57-62. DOI: 10.1038/nature14344.
[15]	WANG SJ, LI D, OU Y, et al. Acetylation is crucial for p53-mediated ferroptosis and tumor suppression[J]. Cell Rep, 2016, 17(2): 366-373. DOI: 10.1016/j.celrep.2016.09.022.
[16]	WANG Y, YANG L, ZHANG X, et al. Epigenetic regulation of ferroptosis by H2B mo- noubiquitination and p53[J]. EMBO Rep, 2019, 20(7): e47563. DOI: 10.15252/embr.201847563.
[17]	MOU Y, ZHANG L, LIU Z, et al. Abundant expression of ferroptosis-related SAT1 is related to unfavorable outcome and immune cell infiltration in low-grade glioma[J]. BMC Cancer, 2022, 22(1): 215. DOI: 10.1186/s12885-022-09313-w.
[18]	MANDAL S, MANDAL A, PARK MH. Depletion of the polyamines spermidine and spermine by overexpression of spermidine/spermine N¹-acetyltransferase 1(SAT1) leads to mitochondria-mediated apoptosis in mammalian cells[J]. Biochem J, 2015, 468(3): 435-447. DOI: 10.1042/BJ20150168.
[19]	OU Y, WANG SJ, LI D, et al. Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses[J]. Proc Natl Acad Sci U S A, 2016, 113(44): E6806-E6812. DOI: 10.1073/pnas.1607152113.
[20]	ZHANG T, CUI Y, WU Y, et al. Mitochondrial GCN5L1 regulates glutaminase acetylation and hepatocellular carcinoma[J]. Clin Transl Med, 2022, 12(5): e852. DOI: 10.1002/ctm2.852.
[21]	HU W, ZHANG C, WU R, et al. Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function[J]. Proc Natl Acad Sci U S A, 2010, 107(16): 7455-7460. DOI: 10.1073/pnas.1001006107.
[22]	SUZUKI S, TANAKA T, POYUROVSKY MV, et al. Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species[J]. Proc Natl Acad Sci U S A, 2010, 107(16): 7461-7466. DOI: 10.1073/pnas.1002459107.
[23]	ZHANG W, GAI C, DING D, et al. Targeted p53 on small-molecules-induced ferroptosis in cancers[J]. Front Oncol, 2018, 8: 507. DOI: 10.3389/fonc.2018.00507.
[24]	XIE Y, ZHU S, SONG X, et al. The tumor suppressor p53 limits ferroptosis by blocking DPP4 activity[J]. Cell Rep, 2017, 20(7): 1692-1704. DOI: 10.1016/j.celrep.2017.07.055.
[25]	VIALE A, de FRANCO F, ORLETH A, et al. Cell-cycle restriction limits DNA damage and maintains self-renewal of leukaemia stem cells[J]. Nature, 2009, 457(7225): 51-56. DOI: 10.1038/nature07618.
[26]	SHAMLOO B, USLUER S. p21 in cancer research[J]. Cancers (Basel), 2019, 11(8): 1178. DOI: 10.3390/cancers11081178.
[27]	TARANGELO A, MAGTANONG L, BIEGING-ROLETT KT, et al. p53 suppresses metabolic stress-in- duced ferroptosis in cancer cells[J]. Cell Rep, 2018, 22(3): 569-575. DOI: 10.1016/j.celrep.2017.12.077.
[28]	XIA X, FAN X, ZHAO M, et al. The relationship between ferroptosis and tumors: a novel landscape for therapeutic approach[J]. Curr Gene Ther, 2019, 19(2): 117-124. DOI: 10.2174/1566523219666190628152137.
[29]	BEKRIC D, OCKER M, MAYR C, et al. Ferroptosis in hepatocellular carcinoma: mec- hanisms, drug targets and approaches to clinical translation[J]. Cancers (Basel), 2022, 14(7): 1826. DOI: 10.3390/cancers14071826.
[30]	LI Y, XIA J, SHAO F, et al. Sorafenib induces mitochondrial dysfunction and exhibits synergistic effect with cysteine depletion by promoting HCC cells ferroptosis[J]. Biochem Biophys Res Commun, 2021, 534: 877-884. DOI: 10.1016/j.bbrc.2020.10.083.
[31]	ZHANG FY, ADILA·YKP, ZHAO JM, et al. Mechanism of ferroptosis and its role in liver diseases[J]. J Clin Hepatol, 2021, 37(6): 1454-1458. DOI: 10.3969/j.issn.1001-5256.2021.06.049. 张飞宇, 阿迪拉·亚克普, 赵金明, 等. 铁死亡的发生机制及在肝脏疾病中的作用[J]. 临床肝胆病杂志, 2021, 37(6): 1454-1458. DOI: 10.3969/j.issn.1001-5256.2021.06.049.
[32]	ZHANG NN, LU W. Targeted therapy for hepatocellular carcinoma[J]. J Clin Hepatol, 2021, 37(8): 1753-1757. DOI: 10.3969/j.issn.1001-5256.2021.08.003. 张宁宁, 陆伟. 肝细胞癌的靶向治疗[J]. 临床肝胆病杂志, 2021, 37(8): 1753-1757. DOI: 10.3969/j.issn.1001-5256.2021.08.003.
[33]	SUN X, NIU X, CHEN R, et al. Metallothionein-1G facilitates sorafenib resistance through inhibition of ferroptosis[J]. Hepatology, 2016, 64(2): 488-500. DOI: 10.1002/hep.28574.
[34]	LI YC, ZHOU Y, WANG X, et al. DHA inhibits proliferation of human hepatocellular carcinoma cells by inducing ferroptosis[J]. Chin J Biochem Mol Biol, 2019, 35(12): 1361-1366. DOI: 10.13865/j.cnki.cjbmb.2019.10.1188. 李艳纯, 周怡, 王鑫, 等. 二氢青蒿素通过诱导铁死亡抑制肝癌细胞生长[J]. 中国生物化学与分子生物学报, 2019, 35(12): 1361-1366. DOI: 10.13865/j.cnki.cjbmb.2019.10.1188.
[35]	LIANG JY, WANG DS, LIN HC, et al. A novel ferroptosis-related gene signature for overall survival prediction in patients with hepatocellular carcinoma[J]. Int J Biol Sci, 2020, 16(13): 2430-2441. DOI: 10.7150/ijbs.45050.