山东大学耳鼻喉眼学报 ›› 2025, Vol. 39 ›› Issue (2): 152-157.doi: 10.6040/j.issn.1673-3770.0.2023.295

• 综述 • 上一篇    

程序性细胞死亡的分子机制和其在鼻咽癌中的作用

吴敏1,2,李正阳1,2,孟杰2,3,叶惠平1,2   

  1. 1.贵州医科大学附属医院 耳鼻咽喉科, 贵州 贵阳 550000;
    2.贵州省人民医院 耳鼻咽喉科, 贵州 贵阳 550002;
    3.遵义医科大学附属医院 耳鼻咽喉科, 贵州 遵义 563000
  • 发布日期:2025-03-26
  • 通讯作者: 叶惠平. E-mail:yehuiping888@aliyun.com

Molecular mechanisms of programmed cell death and its role in nasopharyngeal carcinoma

WU Min1,2, LI Zhengyang1,2, MENG Jie2,3, YE Huiping1,2   

  1. 1. Department of Otolaryngology, The Affiliated Hospital of Guizhou Medical University, Guiyang 550000, Guizhou, China2. Department of Otolaryngology, Guizhou Provincial People's Hospital, Guiyang 550002, Guizhou, China3. Department of Otolaryngology, The Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou, China
  • Published:2025-03-26

摘要: 大约有3/4的鼻咽癌(nasopharyngeal carcinoma, NPC)患者确诊时已处于中晚期。放射及化学疗法是当前NPC的主要疗法,但部分患者的治疗效果并不理想,NPC的分子机制尚不明确。程序性细胞死亡是由一细胞多种主动有序的死亡方式,在生命活动的平衡中发挥着至关重要的作用。近来的研究发现了程序性细胞死亡与NPC相关,铜死亡、铁死亡、焦亡、自噬、坏死性凋亡、细胞凋亡等多种程序性细胞死亡方式在NPC的不同时期发挥着重要作用。本文将概述细胞的铜死亡、铁死亡、焦亡、自噬、坏死性凋亡和细胞凋亡的分子机制和其在NPC发展中的作用,为探索NPC的发病机制和潜在的治疗靶点提供新的视角。

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

Abstract: About 3/4 of patients with nasopharyngeal cancer are diagnosed at an intermediate to advanced stage. Radiation and chemotherapy are the main therapies for NPC. However, the treatment efficacy is not always ideal. The molecular mechanism of NPC remains unclear. Regulated death comprises a variety of active and orderly modes of cell death, and is vital in the balance of life activities. Recent studies have associated regulatory death with NPC. Various modalities of programmed cell death, such as cuproposis, ferroptosis, pyroptosis, autophagy, necroptosis, and apoptosis, play important roles in different NPC stages. This article provides an overview of the molecular mechanisms of cupropopsis, ferroptosis, pyroptosis, autophagy, necroptosis, and apoptosis in cells and their roles in NPC development. The information could provide a new perspective for studies exploring the pathogenesis and potential therapeutic targets of NPC.

Key words: Nasopharyngeal carcinoma, Copper death, Ferroptosis, Death by scorching, Autophagy, Necroptosis, Apoptosis

中图分类号: 

  • R739.63
[1] Chen YP, Chan ATC, Le QT, et al. Nasopharyngeal carcinoma[J]. Lancet, 2019, 394(10192): 64-80. doi:10.1016/S0140-6736(19)30956-0
[2] Yong SK, Ha TC, Yeo MCR, et al. Associations of lifestyle and diet with the risk of nasopharyngeal carcinoma in Singapore: a case-control study[J]. Chin J Cancer, 2017, 36(1): 3. doi:10.1186/s40880-016-0174-3
[3] 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 Cancer J Clin, 2018, 68(6): 394-424. doi:10.3322/caac.21492
[4] Zhang Y, Chen L, Hu GQ, et al. Gemcitabine and cisplatin induction chemotherapy in nasopharyngeal carcinoma[J]. N Engl J Med, 2019, 381(12): 1124-1135. doi:10.1056/NEJMoa1905287
[5] Wong KCW, Hui EP, Lo KW, et al. Nasopharyngeal carcinoma: an evolving paradigm[J]. Nat Rev Clin Oncol, 2021, 18(11): 679-695. doi:10.1038/s41571-021-00524-x
[6] Li YJ, Ou XM, Shen CY, et al. Patterns of local failures and suggestions for reduction of clinical target volume for nasopharyngeal carcinoma patients without cervical lymph node metastasis[J]. OncoTargets Ther, 2018, 11: 2545-2555. doi:10.2147/ott.s158126
[7] Moujalled D, Strasser A, Liddell JR. Molecular mechanisms of cell death in neurological diseases[J]. Cell Death Differ, 2021, 28(7): 2029-2044. doi:10.1038/s41418-021-00814-y
[8] Xu JY, Wei XL, Ren C, et al. Association of plasma epstein-barr virus DNA with outcomes for patients with recurrent or metastatic nasopharyngeal carcinoma receiving anti-programmed cell death 1 immunotherapy[J]. JAMA Netw Open, 2022, 5(3): e220587. doi:10.1001/jamanetworkopen.2022.0587
[9] Yan XW, Wang N, Dong JW, et al. A cuproptosis-related lncRNAs signature for prognosis, chemotherapy, and immune checkpoint blockade therapy of low-grade glioma[J]. Front Mol Biosci, 2022, 9: 966843. doi:10.3389/fmolb.2022.966843
[10] 朱洁洁, 王华. 铜诱导调节性细胞死亡的作用机制与抗肿瘤治疗的研究进展[J]. 江苏大学学报(医学版), 2022, 32(4): 326-331. doi:10.13312/j.issn.1671-7783.y220122
[11] 孙颖, 张斌. 金属配合物作为蛋白酶体抑制剂的研究进展[J]. 化学通报, 2009, 72(6): 495-500. doi:10.14159/j.cnki.0441-3776.2009.06.004 SUN Ying, ZHANG Bin. Progress on organic-metal complexes as proteasome inhibitor[J]. Chemistry, 2009, 72(6): 495-500. doi:10.14159/j.cnki.0441-3776.2009.06.004
[12] Zhou ZJ, Zheng KF, Zhou S, et al. E3 ubiquitin ligases in nasopharyngeal carcinoma and implications for therapies[J]. J Mol Med, 2023, 101(12): 1543-1565. doi:10.1007/s00109-023-02376-7
[13] Li YQ, Chen FF, Chen J, et al. Disulfiram/copper induces antitumor activity against both nasopharyngeal cancer cells and cancer-associated fibroblasts through ROS/MAPK and ferroptosis pathways[J]. Cancers, 2020, 12(1): 138. doi:10.3390/cancers12010138
[14] Kim YJ, Kim JY, Lee N, et al. Disulfiram suppresses cancer stem-like properties and STAT3 signaling in triple-negative breast cancer cells[J]. Biochem Biophys Res Commun, 2017, 486(4): 1069-1076. doi:10.1016/j.bbrc.2017.03.164
[15] Li H, Wang J, Wu C, et al. The combination of disulfiram and copper for cancer treatment[J]. Drug Discov Today, 2020, 25(6): 1099-1108. doi: 10.1016/j.drudis.2020.04.003
[16] Wakisaka N, Wen QH, Yoshizaki T, et al. Association of vascular endothelial growth factor expression with angiogenesis and lymph node metastasis in nasopharyngeal carcinoma[J]. Laryngoscope, 1999, 109(5): 810-814. doi:10.1097/00005537-199905000-00024
[17] 梁勇军, 蒋虹, 金光裕. 贝伐珠单抗疗法在局部晚期及转移性鼻咽癌中的应用[J]. 中国肿瘤临床与康复, 2019, 26(7): 804-807. doi:10.13455/j.cnki.cjcor.2019.07.10
[18] da Silva DA, De Luca A, Squitti R, et al. Copper in tumors and the use of copper-based compounds in cancer treatment[J]. J Inorg Biochem, 2022, 226: 111634. doi:10.1016/j.jinorgbio.2021.111634
[19] Jiang XJ, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease[J]. Nat Rev Mol Cell Biol, 2021, 22(4): 266-282. doi:10.1038/s41580-020-00324-8
[20] 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
[21] Yang WS, Stockwell BR. Ferroptosis: death by lipid peroxidation[J]. Trends Cell Biol, 2016, 26(3): 165-176. doi:10.1016/j.tcb.2015.10.014
[22] Fearnhead HO, Vandenabeele P, Vanden Berghe T. How do we fit ferroptosis in the family of regulated cell death?[J]. Cell Death Differ, 2017, 24(12): 1991-1998. doi:10.1038/cdd.2017.149
[23] Gong CD, Ji QK, Wu MJ, et al. Ferroptosis in tumor immunity and therapy[J]. J Cell Mol Med, 2022, 26(22): 5565-5579. doi:10.1111/jcmm.17529
[24] Angeli JPF, Schneider M, Proneth B, et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice[J]. Nat Cell Biol, 2014, 16(12): 1180-1191. doi:10.1038/ncb3064
[25] Koppula P, Zhuang L, Gan BY. Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy[J]. Protein Cell, 2021, 12(8): 599-620. doi:10.1007/s13238-020-00789-5
[26] Shi M, Du JN, Shi JJ, et al. Ferroptosis-related gene ATG5 is a novel prognostic biomarker in nasopharyngeal carcinoma and head and neck squamous cell carcinoma[J]. Front Bioeng Biotechnol, 2022, 10: 1006535. doi:10.3389/fbioe.2022.1006535
[27] Qiu L, Zhou R, Zhou L, et al. CAPRIN2 upregulation by LINC00941 promotes nasopharyngeal carcinoma ferroptosis resistance and metastatic colonization through HMGCR[J]. Front Oncol, 2022, 12: 931749. doi:10.3389/fonc.2022.931749
[28] Gaggelli E, Kozlowski H, Valensin D, et al. Copper homeostasis and neurodegenerative disorders(Alzheimer's, prion, and Parkinson's diseases and amyotrophic lateral sclerosis)[J]. Chem Rev, 2006, 106(6): 1995-2044. doi:10.1021/cr040410w
[29] Li YQ, Chen FF, Chen J, et al. Disulfiram/copper induces antitumor activity against both nasopharyngeal cancer cells and cancer-associated fibroblasts through ROS/MAPK and ferroptosis pathways[J]. Cancers, 2020, 12(1): 138. doi:10.3390/cancers12010138
[30] Hung CM, Chang CC, Lin CW, et al. GADD45γ induces G2/M arrest in human pharynx and nasopharyngeal carcinoma cells by cucurbitacin E[J]. Sci Rep, 2014, 4: 6454. doi:10.1038/srep06454
[31] Xu Y, Wang Q, Li XZ, et al. Itraconazole attenuates the stemness of nasopharyngeal carcinoma cells via triggering ferroptosis[J]. Environ Toxicol, 2021, 36(2): 257-266. doi:10.1002/tox.23031
[32] Yu P, Zhang X, Liu N, et al. Pyroptosis: mechanisms and diseases[J]. Signal Transduct Target Ther, 2021, 6(1): 128. doi:10.1038/s41392-021-00507-5
[33] Hsu SK, Li CY, Lin IL, et al. Inflammation-related pyroptosis, a novel programmed cell death pathway, and its crosstalk with immune therapy in cancer treatment[J]. Theranostics, 2021, 11(18): 8813-8835. doi:10.7150/thno.62521
[34] Chung IC, Chen LC, Tsang NM, et al. Mitochondrial oxidative phosphorylation complex regulates NLRP3 inflammasome activation and predicts patient survival in nasopharyngeal carcinoma[J]. Mol Cell Proteom, 2020, 19(1): 142-154. doi:10.1074/mcp.RA119.001808
[35] Looi CK, Hii LW, Chung FFL, et al. Roles of inflammasomes in epstein-barr virus-associated nasopharyngeal cancer[J]. Cancers, 2021, 13(8): 1786. doi:10.3390/cancers13081786
[36] Di MP, Miao JJ, Pan QZ, et al. OTUD4-mediated GSDME deubiquitination enhances radiosensitivity in nasopharyngeal carcinoma by inducing pyroptosis[J]. J Exp Clin Cancer Res, 2022, 41(1): 328. doi:10.1186/s13046-022-02533-9
[37] Li Q, Wang M, Zhang Y, et al. BIX-01294-enhanced chemosensitivity in nasopharyngeal carcinoma depends on autophagy-induced pyroptosis[J]. Acta Biochim Biophys Sin, 2020, 52(10): 1131-1139. doi:10.1093/abbs/gmaa097
[38] Wu CW, Wang SG, Lin ML, et al. Downregulation of miR-144 by triptolide enhanced p85α?PTEN complex formation causing S phase arrest of human nasopharyngeal carcinoma cells[J]. Eur J Pharmacol, 2019, 855: 137-148. doi:10.1016/j.ejphar.2019.04.052
[39] Zheng RN, Chen KX, Zhang Y, et al. Apogossypolone induces apoptosis and autophagy in nasopharyngeal carcinoma cells in an in vitro and in vivo study[J]. Oncol Lett, 2017, 14(1): 751-757. doi:10.3892/ol.2017.6176
[40] Glick D, Barth S, MacLeod KF. Autophagy: cellular and molecular mechanisms[J]. J Pathol, 2010, 221(1): 3-12. doi:10.1002/path.2697
[41] Zhu QW, Zhang QC, Gu M, et al. MIR106A-5p upregulation suppresses autophagy and accelerates malignant phenotype in nasopharyngeal carcinoma[J]. Autophagy, 2021, 17(7): 1667-1683. doi:10.1080/15548627.2020.1781368
[42] You B, Xia T, Gu M, et al. AMPK-mTOR-Mediated Activation of Autophagy Promotes Formation of Dormant Polyploid Giant Cancer Cells[J]. Cancer Res, 2022, 82(5): 846-858. doi: 10.1158/0008-5472.CAN-21-2342
[43] 郑传胜, 白薇琦, 俞吉霞, 等. MiR-29调控自噬在鼻咽癌中的研究进展[J]. 现代实用医学, 2022, 34(10): 1388-1390. doi:10.3969/j.issn.1671-0800.2022.10.056
[44] Wang J, Liu GX, Li XJ, et al. Curcumol simultaneously induces both apoptosis and autophagy in human nasopharyngeal carcinoma cells[J]. Phytother Res, 2021, 35(12): 7004-7017. doi:10.1002/ptr.7321
[45] Lin YT, Wang HC, Hsu YC, et al. Capsaicin induces autophagy and apoptosis in human nasopharyngeal carcinoma cells by downregulating the PI3K/AKT/mTOR pathway[J]. Int J Mol Sci, 2017, 18(7): 1343. doi:10.3390/ijms18071343
[46] Degterev A, Hitomi J, Germscheid M, et al. Identification of RIP1 kinase as a specific cellular target of necrostatins[J]. Nat Chem Biol, 2008, 4(5): 313-321. doi:10.1038/nchembio.83
[47] Varfolomeev E, Vucic D. Intracellular regulation of TNF activity in health and disease[J]. Cytokine, 2018, 101: 26-32. doi:10.1016/j.cyto.2016.08.035
[48] Su Z, Yang Z, Xu Y, et al. Apoptosis, autophagy, necroptosis, and cancer metastasis[J]. Mol Cancer, 2015, 14:48. doi: 10.1186/s12943-015-0321-5
[49] Rao Z, Zhu Y, Yang P, et al. Pyroptosis in inflammatory diseases and cancer[J]. Theranostics, 2022, 12(9): 4310-4329. doi: 10.7150/thno.71086
[50] Siegmund D, Wagner J, Wajant H. TNF receptor associated factor 2(TRAF2)signaling in cancer[J]. Cancers, 2022, 14(16): 4055. doi:10.3390/cancers14164055
[51] Bao CH, Sun Y, Dwarakanath B, et al. Carbon ion triggered immunogenic necroptosis of nasopharyngeal carcinoma cells involving necroptotic inhibitor BCL-X[J]. J Cancer, 2021, 12(5): 1520-1530. doi:10.7150/jca.46316
[52] Deng Q, Yu X, Xiao L, et al. Neoalbaconol induces energy depletion and multiple cell death in cancer cells by targeting PDK1-PI3-K/Akt signaling pathway[J]. Cell Death Dis, 2013, 4(9): e804. doi: 10.1038/cddis.2013.324
[53] Liu TC, Sun X, Cao ZW. Shikonin-induced necroptosis in nasopharyngeal carcinoma cells via ROS overproduction and upregulation of RIPK1/RIPK3/MLKL expression[J]. Onco Targets Ther, 2019, 12: 2605-2614. doi:10.2147/OTT.S200740
[54] Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics[J]. Br J Cancer, 1972, 26(4): 239-257. doi:10.1038/bjc.1972.33
[55] Fleisher TA. Apoptosis[J]. Ann Allergy Asthma Immunol, 1997, 78(3): 245-249. doi:10.1016/S1081-1206(10)63176-6
[56] Kashyap D, Garg VK, Goel N. Intrinsic and extrinsic pathways of apoptosis: role in cancer development and prognosis[J]. Adv Protein Chem Struct Biol, 2021, 125: 73-120. doi:10.1016/bs.apcsb.2021.01.003
[57] Tang M, Dong X, Xiao LB, et al. CPT1A-mediated fatty acid oxidation promotes cell proliferation via nucleoside metabolism in nasopharyngeal carcinoma[J]. Cell Death Dis, 2022, 13(4): 331. doi:10.1038/s41419-022-04730-y
[58] Qi CL, Huang ML, Zou Y, et al. The IRF2/CENP-N/AKT signaling axis promotes proliferation, cell cycling and apoptosis resistance in nasopharyngeal carcinoma cells by increasing aerobic glycolysis[J]. J Exp Clin Cancer Res, 2021, 40(1): 390. doi:10.1186/s13046-021-02191-3
[59] Liang YS, Feng GF, Wu L, et al. Caffeic acid phenethyl ester suppressed growth and metastasis of nasopharyngeal carcinoma cells by inactivating the NF-κB pathway[J]. Drug Des Dev Ther, 2019, 13: 1335-1345. doi:10.2147/dDDT.s199182
[60] Wang TT, Chen ZZ, Xie P, et al. Isoliquiritigenin suppresses the proliferation and induced apoptosis via miR-32/LATS2/Wnt in nasopharyngeal carcinoma[J]. Eur J Pharmacol, 2019, 856: 172352. doi: 10.1016/j.ejphar.2019.04.033
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