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.

中文翻译：

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氨基酸和单羧酸盐转运蛋白的和谐相互作用诱导癌细胞的健壮性

越来越多的证据表明，代谢重编程有助于获得和维持与恶性肿瘤相关的健壮性。氨基酸和单羧酸盐转运蛋白表达水平的精细调节使癌细胞能够表现出引起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可吸收和输出胱氨酸和谷氨酰胺等氨基酸，从而调节谷胱甘肽的合成，自噬和谷氨酰胺分解。CD44变体是一种癌症干细胞样的细胞标志物，可稳定细胞膜上的xCT反转运蛋白，并且对xCT和/或ASCT2呈阳性的肿瘤细胞对系统Xc（-）抑制剂柳氮磺吡啶类药物敏感。抑制LAT1和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（mTOR）复合物1的哺乳动物靶标。由LAT1调节的mTOR信号传导是营养肿瘤微环境动态变化的传感器。LAT1在各种恶性肿瘤中过表达，并且与不良的临床结果呈正相关。谷氨酰胺的代谢重编程通常发生在癌细胞中，表现为ASCT2介导的谷氨酰胺成瘾。单羧酸盐转运蛋白（MCTs）介导代谢共生，低氧环境下癌细胞中的乳酸通过MCT4出口，并由MCT1引入到低氧区域，在该区域用作氧化代谢产物。转运蛋白的差异表达模式引起功能性肿瘤内异质性，导致治疗耐药性。因此，基于这些转运蛋白的代谢重编程可能是有前途的治疗目标。这篇综述重点介绍了转运蛋白（包括xCT，ASCT2，LAT1和MCT）的病理功能和治疗靶点。