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肿瘤代谢与营养电子杂志
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单羧酸转运载体与肿瘤代谢的关系
1,2陈哲文,3张杰,4王正平,5宋蒙蒙,6张启瑜,7缪明永,1石汉平
1首都医科大学附属北京世纪坛医院胃肠外科/临床营养科,北京 100038; 2温州医科大学附属第二医院,浙江 温州 325000;3徐州医科大学附属淮安医院,江苏 淮安 223002; 4聊城大学生物制药研究院, 山东 聊城 252059;5郑州大学,河南 郑州 450000;6温州医科大学附属第一医院, 浙江 温州 325000;7第二军医大学基础医学部生物化学与分子生物学教研室,上海 200433
The relationship between monocarboxylate transporter and tumor metabolism
1,2Chen Zhe-wen,3Zhang Jie4, Wang Zheng-ping,5Song Meng-meng,6Zhang Qi-yu, 7Miao Ming-yong,1Shi Han-ping
1Department of Clinical Nutrition/Gastrointestinal Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China;2The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China; 3The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an 223002,Jiangsu, China; 4Institute of BioPharmaccutical Research, Liaocheng University, Liaochen 252059, Shandong, China;5Zhengzhou University, Zhengzhou 450000, Henan, China;6The First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China;7Department of Biochemistry and Molecular Biology, The College of Basic Medical Sciences, The Second Military Medical University, Shanghai 200433, China
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摘要 单羧酸转运载体是一类重要的跨膜转运蛋白,它们负责单羧酸类物质如丙酮酸、乳酸、酮体等的跨膜转运,具有促进这些物质的营养吸收,维持细胞代谢平衡等功能。单羧酸转运载体在肿瘤中的表达明显上调,与糖代谢、脂代谢、能量代谢途径及肿瘤微环境的形成密切相关,对维持肿瘤细胞高糖酵解状态具有重要作用。在一些肿瘤中,乳酸由低氧区的糖酵解癌细胞产生,通过单羧酸转运载体4排出到肿瘤微环境中,然后被表达单羧酸转运载体1的外周氧化型癌细胞摄取,进入TCA循环成为呼吸作用的燃料。丙酮酸也通过单羧酸转运载体1和单羧酸转运载体2外排到肿瘤细胞外,而肿瘤微环境中的丙酮酸能够促进乳腺癌的肺转移。同时,单羧酸转运载体促进酸性的肿瘤微环境形成,这不仅有利于肿瘤的生长、增殖及转移,还会导致肿瘤周围正常细胞的死亡,肿瘤的免疫抑制也与这有关。目前已有多项研究证实了单羧酸转运载体1和单羧酸转运载体4的高表达与肿瘤恶性程度及预后呈正相关,抑制单羧酸转运载体的表达可以抑制肿瘤的生长、增殖及转移,这为肿瘤的靶向治疗提供了潜在的治疗靶点。目前已有的单羧酸转运载体抑制剂如CHC、AR-C155858和AZD3965对单羧酸转运载体各型的选择性较差,但已经显示出了良好治疗效果。开发新型单羧酸转运载体抑制剂的同时,探索与传统肿瘤疗法联合应用的策略具有不错的临床应用前景。
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陈哲文
张杰
王正平
宋蒙蒙
张启瑜
缪明永
石汉平
关键词 单羧酸转运载体肿瘤代谢糖酵解靶向治疗    
Abstract:Monocarboxylate transporters (MCTs) are important transmembrane transporters responsible for monocarboxylate metabolites such as pyruvate, lactate, ketone bodies. They promote nutrient absorption of these substances and maintain the metabolic balance of cells. The expression of MCT in tumors is significantly up-regulated, which is closely related to glucose metabolism, lipid metabolism, energy metabolism and the formation of tumor microenvironment, and plays an essential role in maintaining the high glycolytic state of tumor cells. In some tumors, lactic acid is produced by glycolytic cells in the hypoxic region, excreted into the tumor microenvironment by MCT4, and then taken up by peripheral oxidized cells expressing MCT1, finally enters the TCA cycle and becomes a fuel for respiration. Pyruvate is also effluxed out of tumor cells by MCT1 and MCT2, while pyruvate in the tumor microenvironment promotes lung metastasis of breast cancer. At the same time, MCT promotes the formation of acidic tumor microenvironment, which is not only conducive to the growth, proliferation and metastasis of tumors, but also causes the death of normal cells around the tumor. The immunosuppression of tumors is also related to this. A number of studies have proved that the high expression of MCT1 and MCT4 is positively correlated with tumor malignancy and prognosis. Inhibition of MCT expression influences tumor growth, proliferation and metastasis, which provides potential therapeutic targets for targeted therapy. Currently MCT inhibitors such as CHC, AR-C155858 and AZD3965 are lack of selectivity for MCT subtypes, but have shown good therapeutic effects. While developing new MCT inhibitors, exploring strategies for joint application with traditional tumor therapies has a good clinical application prospect.
Key wordsMCT    Tumor metabolism    Glycolysis    Targeted therapy
    
通讯作者: 石汉平,电子邮箱:shihp@ccmu.edu.cn;缪明永,电子邮箱:miaomy@163.com;张启瑜,电子邮箱:qiyuz@126.com   
引用本文:   
陈哲文,张杰,王正平,宋蒙蒙,张启瑜,缪明永,石汉平. 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.
Chen Zhe-wen,Zhang Jie, Wang Zheng-ping,Song Meng-meng,Zhang Qi-yu, Miao Ming-yong,Shi Han-ping. The relationship between monocarboxylate transporter and tumor metabolism. Electron J Metab Nutr Cancer, 2019, 6(2): 266-271.