Yoshida Go J
Department of Immunological Diagnosis, Juntendo University Graduate School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Metabolites. 2021 Jan 2;11(1):27. doi: 10.3390/metabo11010027.
There is a growing body of evidence that metabolic reprogramming contributes to the acquisition and maintenance of robustness associated with malignancy. The fine regulation of expression levels of amino acid and monocarboxylate transporters enables cancer cells to exhibit the metabolic reprogramming that is responsible for therapeutic resistance. Amino acid transporters characterized by xCT (SLC7A11), ASCT2 (SLC1A5), and LAT1 (SLC7A5) function in the uptake and export of amino acids such as cystine and glutamine, thereby regulating glutathione synthesis, autophagy, and glutaminolysis. CD44 variant, a cancer stem-like cell marker, stabilizes the xCT antiporter at the cellular membrane, and tumor cells positive for xCT and/or ASCT2 are susceptible to sulfasalazine, a system Xc(-) inhibitor. Inhibiting the interaction between LAT1 and CD98 heavy chain prevents activation of the mammalian target of rapamycin (mTOR) complex 1 by glutamine and leucine. mTOR signaling regulated by LAT1 is a sensor of dynamic alterations in the nutrient tumor microenvironment. LAT1 is overexpressed in various malignancies and positively correlated with poor clinical outcome. Metabolic reprogramming of glutamine occurs often in cancer cells and manifests as ASCT2-mediated glutamine addiction. Monocarboxylate transporters (MCTs) mediate metabolic symbiosis, by which lactate in cancer cells under hypoxia is exported through MCT4 and imported by MCT1 in less hypoxic regions, where it is used as an oxidative metabolite. Differential expression patterns of transporters cause functional intratumoral heterogeneity leading to the therapeutic resistance. Therefore, metabolic reprogramming based on these transporters may be a promising therapeutic target. This review highlights the pathological function and therapeutic targets of transporters including xCT, ASCT2, LAT1, and MCT.
越来越多的证据表明，代谢重编程有助于恶性肿瘤获得并维持其强大的特性。氨基酸和单羧酸转运蛋白表达水平的精细调节使癌细胞能够展现出导致治疗抗性的代谢重编程。以xCT（SLC7A11）、ASCT2（SLC1A5）和LAT1（SLC7A5）为特征的氨基酸转运蛋白在胱氨酸和谷氨酰胺等氨基酸的摄取和输出中发挥作用，从而调节谷胱甘肽合成、自噬和谷氨酰胺分解代谢。CD44变体是一种癌症干细胞样细胞标志物，可使xCT反向转运蛋白在细胞膜上稳定，而xCT和/或ASCT2呈阳性的肿瘤细胞对柳氮磺胺吡啶（一种系统Xc(-)抑制剂）敏感。抑制LAT1与CD98重链之间的相互作用可防止谷氨酰胺和亮氨酸激活雷帕霉素哺乳动物靶标（mTOR）复合物1。由LAT1调节的mTOR信号传导是营养性肿瘤微环境动态变化的传感器。LAT1在各种恶性肿瘤中均过度表达，且与不良临床结果呈正相关。谷氨酰胺的代谢重编程在癌细胞中经常发生，并表现为ASCT2介导的谷氨酰胺成瘾。单羧酸转运蛋白（MCTs）介导代谢共生，即缺氧条件下癌细胞中的乳酸通过MCT4输出，并由MCT1在低氧区域摄取，在那里它被用作氧化代谢物。转运蛋白的差异表达模式导致肿瘤内功能异质性，从而产生治疗抗性。因此，基于这些转运蛋白的代谢重编程可能是一个有前景的治疗靶点。本综述重点介绍了包括xCT、ASCT2、LAT1和MCT在内的转运蛋白的病理功能和治疗靶点。
