单羧酸转运载体与肿瘤代谢的关系

The relationship between monocarboxylate transporter and tumor metabolism

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。

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.