ABCG2, a member of the ABC transporter superfamily, is overexpressed in many human tumors and has long been studied for its ability to export a variety of chemotherapeutic agents, thereby conferring a multidrug resistance (MDR) phenotype. However, several studies have shown that ABCG2 can also confer an MDR- survival advantage to tumor cells exposed to stress. While investigating the mechanism by which ABCG2 enhances survival in stressful milieus, we have identified a physical and functional interaction between ABCG2 and SLC1A5, a member of the solute transporter superfamily and the primary transporter of glutamine in cancer cells. This interaction was accompanied by increased glutamine uptake, increased glutaminolysis, and rewired cellular metabolism, as evidenced by an increase in key metabolic enzymes and alteration of glutamine-dependent metabolic pathways. Specifically, we observed an increase in glutamine metabolites shuttled to the TCA cycle, and an increase in the synthesis of glutathione, accompanied by a decrease in basal levels of reactive oxygen species and a marked increase in cell survival in the face of oxidative stress. Notably, the knockdown of SLC1A5 or depletion of exogenous glutamine diminished ABCG2-enhanced autophagy flux, further implicating this solute transporter in ABCG2-mediated cell survival. This is, to our knowledge, the first report of a functionally significant physical interaction between members of the two major transporter superfamilies. Moreover, these observations may underlie the protective role of ABCG2 in cancer cells under duress and suggest a novel role for ABCG2 in the regulation of metabolism in normal and diseased states.

中文翻译：

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ABCG2 和 SLC1A5 功能上相互作用，重新连接代谢并赋予癌细胞在氧化应激下的生存优势


ABCG2 是 ABC 转运蛋白超家族的成员，在许多人类肿瘤中过度表达，长期以来一直研究其输出多种化疗药物的能力，从而赋予多药耐药性 (MDR) 表型。然而，一些研究表明 ABCG2 也可以赋予暴露于压力的肿瘤细胞 MDR 生存优势。在研究 ABCG2 增强应激环境中生存的机制时，我们发现了 ABCG2 和 SLC1A5 之间的物理和功能相互作用，SLC1A5 是溶质转运蛋白超家族的成员，也是癌细胞中谷氨酰胺的主要转运蛋白。这种相互作用伴随着谷氨酰胺摄取增加、谷氨酰胺分解增加和细胞代谢重新连接，关键代谢酶的增加和谷氨酰胺依赖性代谢途径的改变证明了这一点。具体来说，我们观察到穿梭至 TCA 循环的谷氨酰胺代谢物增加，谷胱甘肽合成增加，伴随着活性氧基础水平的降低以及面对氧化应激的细胞存活率显着增加。值得注意的是，SLC1A5 的敲低或外源谷氨酰胺的消耗减少了 ABCG2 增强的自噬通量，进一步表明这种溶质转运蛋白与 ABCG2 介导的细胞存活有关。据我们所知，这是关于两个主要转运蛋白超家族成员之间具有重要功能的物理相互作用的第一份报告。此外，这些观察结果可能是ABCG2在胁迫下的癌细胞中发挥保护作用的基础，并表明ABCG2在正常和患病状态下的代谢调节中具有新的作用。