单羧酸转运蛋白家族与头颈部鳞状细胞癌的研究进展

doi:10.6040/j.issn.1673-3770.0.2020.196

摘要/Abstract

摘要： 单羧酸转运蛋白家族(MCTs)参与肿瘤代谢调节,对细胞的乳酸、丙酮酸、酮体等物质起转运作用,在不同的肿瘤细胞中表达出不同的亚型。家族内的MCT1和MCT4及其伴侣蛋白CD147、葡萄糖转运蛋白GLUT-1、缺氧生物标记碳酸酐酶9(CAIX)在鼻咽癌、喉癌、口腔鳞状细胞癌等头颈部鳞状细胞癌中均发挥了重要作用。针对头颈鳞状细胞癌中MCTs不同的亚型采取靶向治疗及与其他治疗方式联合治疗以取得更好的疗效是未来的研究方向。就MCTs在头颈部鳞状细胞癌发生发展的作用机制及以MCTs作为靶点进行治疗的研究现状做综述。

关键词: 单羧酸转运蛋白, 代谢, 乳酸, 抑制剂

Abstract: The family of monocarboxylate transporters(MCTs)is involved in regulating tumor metabolism. Specifically, such proteins play a role in transporting lactic acid, pyruvate, ketone bodies, and other metabolites in cells. Various MCT isoforms are highly-expressed across different tumor cells. Family members MCT1 and MCT4 in conjunction with associated chaperones basigin(CD147)and glucose transporter type 1(GLUT-1), as well as the anoxia biomarker carbonic anhydrase 9(CAIX), all play important roles in head and neck squamous cell carcinomas(HNSCCs), including nasopharyngeal, laryngeal, and oral squamous cell carcinomas. Combining MCT modulation with existing therapies has the potential to improve HNSCC treatment efficacy. This review discusses the mechanisms by which MCTs contribute to development of HNSCC and the current state of research regarding MCT therapeutic targeting.

Key words: Monocarboxylate transporter, Metabolism, Lactic acid, Inhibitor

中图分类号:

R762

马小雨,边晓敏,于丹. 单羧酸转运蛋白家族与头颈部鳞状细胞癌的研究进展[J]. 山东大学耳鼻喉眼学报, 2021, 35(2): 125-130.

MA Xiaoyu, BIAN Xiaomin,YU Dan. Advances in understanding the roles of monocarboxylate transporters in head and neck squamous cell carcinoma[J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2021, 35(2): 125-130.

参考文献

[1] Halestrap AP. The monocarboxylate transporter family: Structure and functional characterization[J]. IUBMB Life, 2012, 64(1): 1-9. doi:10.1002/iub.573.
[2] 陈哲文, 张杰, 王正平, 等. 单羧酸转运载体与肿瘤代谢的关系[J]. 肿瘤代谢与营养电子杂志, 2019,6(2):266-271. doi:10.16689/j.cnki.cn11-9349/r.2019.02.021. CHEN Zhewen, ZHANG Jie, WANG Zhengping, et al. The relationship between monocarboxylate transporter and tumor metabolism[J]. Electronic Jourmal of Metabolism and Nutrition of Cancer, 2019,6(2):266-271. doi:10.16689/j.cnki.cn11-9349/r.2019.02.021.
[3] Payen VL, Mina E, van Hée VF, et al. Monocarboxylate transporters in cancer[J]. Mol Metab, 2020, 33: 48-66. doi:10.1016/j.molmet.2019.07.006.
[4] Blatt S, Voelxen N, Sagheb K, et al. Lactate as a predictive marker for tumor recurrence in patients with head and neck squamous cell carcinoma(HNSCC)post radiation: a prospective study over 15 years[J]. Clin Oral Investig, 2016, 20(8): 2097-2104. doi:10.1007/s00784-015-1699-6.
[5] Cappelletti V, Iorio E, Miodini P, et al. Metabolic footprints and molecular subtypes in breast cancer[J]. Dis Markers, 2017, 2017: 7687851. doi:10.1155/2017/7687851.
[6] Pérez-Escuredo J, van Hée VF, Sboarina M, et al. Monocarboxylate transporters in the brain and in cancer[J]. Biochim Biophys Acta, 2016, 1863(10): 2481-2497. doi:10.1016/j.bbamcr.2016.03.013.
[7] Dovmark TH, Saccomano M, Hulikova A, et al. Connexin-43 channels are a pathway for discharging lactate from glycolytic pancreatic ductal adenocarcinoma cells[J]. Oncogene, 2017, 36(32): 4538-4550. doi:10.1038/onc.2017.71.
[8] Marchiq I, Pouysségur J. Hypoxia, cancer metabolism and the therapeutic benefit of targeting lactate/H+ symporters[J]. J Mol Med, 2016, 94(2): 155-171. doi:10.1007/s00109-015-1307-x.
[9] Hong CS, Graham NA, Gu W, et al. MCT1 modulates cancer cell pyruvate export and growth of tumors that Co-express MCT1 and MCT4[J]. Cell Rep, 2016, 14(7): 1590-1601. doi:10.1016/j.celrep.2016.01.057.
[10] Huang D, Li TT, Wang L, et al. Hepatocellular carcinoma redirects to ketolysis for progression under nutrition deprivation stress[J]. Cell Res, 2016, 26(10): 1112-1130. doi:10.1038/cr.2016.109.
[11] Zhang J, Jia PP, Liu QL, et al. Low ketolytic enzyme levels in tumors predict ketogenic diet responses in cancer cell lines in vitro and in vivo[J]. J Lipid Res, 2018, 59(4): 625-634. doi:10.1194/jlr.M082040.
[12] Domingo-Vidal M, Whitaker-Menezes D, Martos-Rus C, et al. Cigarette smoke induces metabolic reprogramming of the tumor stroma in head and neck squamous cell carcinoma[J]. Mol Cancer Res, 2019, 17(9): 1893-1909. doi:10.1158/1541-7786.MCR-18-1191.
[13] Yoshida GJ. Metabolic reprogramming: the emerging concept and associated therapeutic strategies[J]. J Exp Clin Cancer Res, 2015, 34: 111. doi:10.1186/s13046-015-0221-y.
[14] Doherty JR, Cleveland JL. Targeting lactate metabolism for cancer therapeutics[J]. J Clin Invest, 2013, 123(9): 3685-3692. doi:10.1172/JCI69741.
[15] Seminerio I, Kindt N, Descamps G, et al. High infiltration of CD68+ macrophages is associated with poor prognoses of head and neck squamous cell carcinoma patients and is influenced by human papillomavirus[J]. Oncotarget, 2018, 9(13): 11046-11059. doi:10.18632/oncotarget.24306.
[16] Chung CH, Zhang Q, Kong CS, et al. P16 protein expression and human papillomavirus status as prognostic biomarkers of nonoropharyngeal head and neck squamous cell carcinoma[J]. J Clin Oncol, 2014, 32(35): 3930-3938. doi:10.1200/jco.2013.54.5228.
[17] Fleming JC, Woo J, Moutasim K, et al. HPV, tumour metabolism and novel target identification in head and neck squamous cell carcinoma[J]. Br J Cancer, 2019, 120(3): 356-367. doi:10.1038/s41416-018-0364-7.
[18] 陈蓓. 人乳头状瘤病毒及pRb在头颈鳞状细胞癌中的表达[J]. 临床耳鼻咽喉科杂志, 2004, 18(3): 154-156. doi: 10.3969/j.issn.1001-1781.2004.03.012. CHEN Bei. Expression of human papillomavirus and pRb in head and neck squamous cell carcinoma[J]. Journal of Clinical Otorhinolaryngology, 2004, 18(3): 154-156.doi: 10.3969/j.issn.1001-1781.2004.03.012.
[19] Doherty JR, Cleveland JL. Targeting lactate metabolism for cancer therapeutics[J]. J Clin Invest, 2013, 123(9): 3685-3692. doi:10.1172/JCI69741.
[20] Khammanivong A, Saha J, Spartz AK, et al. A novel MCT1 and MCT4 dual inhibitor reduces mitochondrial metabolism and inhibits tumour growth of feline oral squamous cell carcinoma[J]. Vet Comp Oncol,2019:29. doi: 10.1111/vco.12551. Online ahead of print.
[21] 张配, 刘芳, 高娇, 等. 抑制单羧酸转运蛋白1可增强鼻咽癌细胞HNE1/DDP对顺铂诱导凋亡的敏感性[J]. 南方医科大学学报,2017,37(7):883-888. doi: 10.3969/j.issn.1673-4254.2017.07.05. ZHANG Pei, LIU Fang, GAO Jiao, et al. Small interfering RNA-mediated monocarboxylate transporter 1 silencing enhances sensitivity of nasopharyngeal carcinoma HNE1/DDP cells to cisplatin-induced apoptosis[J]. Journal of Southern Medical University,2017,37(7):883-888. doi: 10.3969/j.issn.1673-4254.2017.07.05.
[22] 张剑利, 陈伟雄, 陈瑞开, 等. 鼻咽癌放疗后远期吞咽功能的纤维喉镜评估[J]. 山东大学耳鼻喉眼学报,2019,33(6):56-59. doi: 10.6040/j.issn.1673-3770.0.2019.316. ZHANG Jianli, CHEN Weixiong, CHEN Ruikai, et al. Evaluation of the effect of fiberoptic endoscopic evaluation of swallowing on long-term survivor with nasopharyngeal cancer[J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2019, 33(6):56-59. doi: 10.6040/j.issn.1673-3770.0.2019.316.
[23] Gray AL, Coleman DT, Shi RH, et al. Monocarboxylate transporter 1 contributes to growth factor-induced tumor cell migration independent of transporter activity[J]. Oncotarget, 2016, 7(22): 32695-32706. doi:10.18632/oncotarget.9016.
[24] Feldman R, Gatalica Z, Knezetic J, et al. Molecular profiling of head and neck squamous cell carcinoma[J]. Head Neck, 2016, 38(Suppl 1): E1625-E1638. doi:10.1002/hed.24290.
[25] 王亚波, 徐鸥, 张瑞敬, 等. GLUT-1和MCT-4与CAⅨ在喉鳞状细胞癌中的初步研究[J].临床耳鼻咽喉头颈外科杂志,2017,31(7):510-514. doi: 10.13201/j.issn.1001-1781.2017.07.005. WANG Yabo, XU Ou, ZHANG Ruijing, et al. A preliminary study on the relationship between GLUT-1, MCT-4 and CA Ⅸ in laryngeal squamous cell carcinoma[J]. Journal of Clinical Otorhinolaryngology Head and Neck Surgery, 2017, 31(7):510-514. doi: 10.13201/j.issn.1001-1781.2017.07.005.
[26] 王亚波, 徐鸥, 张瑞敬, 等. 喉鳞状细胞癌中p53与MCT-1的相关性研究[J]. 临床耳鼻咽喉头颈外科杂志, 2017(11): 825-829. doi:10.13201/j.issn.1001-1781.2017.11.003. WANG Yabo, XU Ou, ZHANG Ruijing, et al. Study on the relationship between MCT-1 and p53 in laryngeal squamous cell carcinoma[J]. Journal of Clinical Otorhinolaryngology, 2017,31(11): 825-829. doi:10.13201/j.issn.1001-1781.2017.11.003.
[27] Simões-Sousa S, Granja S, Pinheiro C, et al. Prognostic significance of monocarboxylate transporter expression in oral cavity tumors[J]. Cell Cycle, 2016, 15(14): 1865-1873. doi:10.1080/15384101.2016.1188239.
[28] Halestrap AP. The SLC16 gene family-structure, role and regulation in health and disease[J]. Mol Aspects Med, 2013, 34(2/3): 337-349. doi:10.1016/j.mam.2012.05.003.
[29] Khammanivong A, Saha J, Spartz AK, et al. A novel MCT1 and MCT4 dual inhibitor reduces mitochondrial metabolism and inhibits tumour growth of feline oral squamous cell carcinoma[J]. Vet Comp Oncol, 2019,29. doi:10.1111/vco.12551.
[30] 王仲崑, 张配, 潘琼, 等. 单羧酸转运蛋白1抑制剂AZD3965对胃癌BCG-823细胞增殖和凋亡的影响[J]. 蚌埠医学院学报,2018,43(12):1541-1545. doi: 10.13898/j.cnki.issn.1000-2200.2018.12.001. WANG Zhongkun, ZHANG Pei, PAN Qiong, et al. Effect of monocarboxylate transporter 1 inhibitor AZD3965 on the proliferation and apoptosis of gastric cancer BCG-823 cells[J]. Journal of Bengbu Medical College,2018,43(12):1541-1545. doi: 10.13898/j.cnki.issn.1000-2200.2018.12.001.
[31] Mehibel M, Ortiz-Martinez F, Voelxen N, et al. Statin-induced metabolic reprogramming in head and neck cancer: a biomarker for targeting monocarboxylate transporters[J]. Sci Rep, 2018, 8(1): 16804. doi:10.1038/s41598-018-35103-1.
[32] Beloueche-Babari M, Wantuch S, Casals Galobart T, et al. MCT1 inhibitor AZD3965 increases mitochondrial metabolism, facilitating combination therapy and noninvasive magnetic resonance spectroscopy[J]. Cancer Res, 2017, 77(21): 5913-5924. doi:10.1158/0008-5472.CAN-16-2686.
[33] Quanz M, Bender E, Kopitz C, et al. Preclinical efficacy of the novel monocarboxylate transporter 1 inhibitor BAY-8002 and associated markers of resistance[J]. Mol Cancer Ther, 2018, 17(11): 2285-2296. doi:10.1158/1535-7163.MCT-17-1253.
[34] Ovens MJ, Davies AJ, Wilson MC, et al. AR-C155858 is a potent inhibitor of monocarboxylate transporters MCT1 and MCT2 that binds to an intracellular site involving transmembrane helices 7-10[J]. Biochem J, 2010, 425(3): 523-530. doi:10.1042/BJ20091515.
[35] 程泽鹏, 冯钰, 史仍飞. 运动过程中单羧酸转运蛋白(MCTs)作用的研究进展[J].军事体育学报,2017,36(3):89-94. doi: 10.3969/j.issn.1671-1300.2017.03.025. CHENG Zepeng, FENG Yu, SHI Rengfei. Research on MCTs Function during the Exercise.[J]. Journal of Military Physical Education and Sports, 2017, 36(3): 89-94. doi:10.3969/j.issn.1671-1300.2017.03.025.
[36] Vijay N, Morse BL, Morris ME. A novel monocarboxylate transporter inhibitor as a potential treatment strategy for γ-hydroxybutyric acid overdose[J]. Pharm Res, 2015, 32(6): 1894-1906. doi:10.1007/s11095-014-1583-0.
[37] Payen VL, Mina E, van Hée VF, et al. Monocarboxylate transporters in cancer[J]. Mol Metab, 2020, 33: 48-66. doi:10.1016/j.molmet.2019.07.006.
[38] Curtis NJ, Mooney L, Hopcroft L, et al. Pre-clinical pharmacology of AZD3965, a selective inhibitor of MCT1: DLBCL, NHL and Burkitt's lymphoma anti-tumor activity[J]. Oncotarget, 2017, 8(41): 69219-69236. doi:10.18632/oncotarget.18215.
[39] Pérez-Escuredo J, van Hée VF, Sboarina M, et al. Monocarboxylate transporters in the brain and in cancer[J]. Biochim Biophys Acta, 2016, 1863(10): 2481-2497. doi:10.1016/j.bbamcr.2016.03.013.
[40] Lebo NL, Griffiths R, Hall S, et al. Effect of statin use on oncologic outcomes in head and neck squamous cell carcinoma[J]. Head Neck, 2018, 40(8): 1697-1706. doi:10.1002/hed.25152.
[41] Mehibel M, Ortiz-Martinez F, Voelxen N, et al. Statin-induced metabolic reprogramming in head and neck cancer: a biomarker for targeting monocarboxylate transporters[J]. Sci Rep, 2018, 8(1): 16804. doi:10.1038/s41598-018-35103-1.
[42] Cho SJ, Kim JS, Kim JM, et al. Simvastatin induces apoptosis in human colon cancer cells and in tumor xenografts, and attenuates colitis-associated colon cancer in mice[J]. Int J Cancer, 2008, 123(4): 951-957. doi:10.1002/ijc.23593.

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