SLC38A2过表达诱导癌症样代谢特征，并与SLC1A5合作用于全癌预后,Chemistry - An Asian Journal

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SLC38A2过表达诱导癌症样代谢特征，并与SLC1A5合作用于全癌预后
Chemistry - An Asian Journal ( IF 3.5 ) Pub Date : 2020-09-29 , DOI: 10.1002/asia.202001056
Meng‐Sen Huang, Jen‐Hsuan Chang, Wen‐Ching Lin, Yu‐Hsiang Cheng, Fu‐An Li, Ching‐Shu Suen, Ming‐Jing Hwang, Chung‐ke Chang, Kurt Yun Mou

癌细胞大大增加了对能量以及生物合成前体的需求，以促进其不安定的生长。增强的谷氨酰胺分解是满足这些需求的癌症代谢的标志。先前有报道说，有争议的观点是，两种谷氨酰胺转运蛋白SLC1A5和SLC38A2可以促进癌症中的谷氨酰胺分解。在这项研究中，我们利用基于质谱的蛋白质组学利用邻近标记反应绘制蛋白质相互作用组图谱，并发现了SLC1A5和SLC38A2之间潜在的蛋白质相互作用。通过双分子荧光互补测定进一步证实了SLC1A5 / SLC38A2的相互作用。我们进一步研究了SLC1A5和SLC38A2在人体细胞中过表达的代谢影响，发现只有SLC38A2而非SLC1A5，结果导致了类似癌症的新陈代谢，通过核磁共振波谱定量分析，细胞内必需氨基酸和乳酸的浓度显着增加。最后，我们分析了一个大型癌症人群的5年生存率，发现SLC1A5^hi / SLC38A2 ^lo组与低存活率无关，而SLC1A5 ^lo / SLC38A2 ^hi组明显增加了致死率。有趣的是，SLC1A5 ^hi / SLC38A2 ^hi组的预后甚至更差，表明SLC1A5与SCL38A2之间具有协同作用。我们的数据表明，SLC38A2在重编程类癌的新陈代谢和促进癌症进展中起主要作用，而SLC1A5与SLC38A2共表达时可能会增强这种作用。我们提出了一个模型来解释SLC1A5，SLC38A2和SCL7A5之间的关系，并讨论它们对谷氨酰胺分解和mTOR信号传导的影响。

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SLC38A2 Overexpression Induces a Cancer‐like Metabolic Profile and Cooperates with SLC1A5 in Pan‐cancer Prognosis

Cancer cells have dramatically increased demands for energy as well as biosynthetic precursors to fuel their restless growth. Enhanced glutaminolysis is a hallmark of cancer metabolism which fulfills these needs. Two glutamine transporters, SLC1A5 and SLC38A2, have been previously reported to promote glutaminolysis in cancer with controversial perspectives. In this study, we harnessed the proximity labeling reaction to map the protein interactome using mass spectrometry‐based proteomics and discovered a potential protein‐protein interaction between SLC1A5 and SLC38A2. The SLC1A5/SLC38A2 interaction was further confirmed by bimolecular fluorescence complementation assay. We further investigated the metabolic influence of SLC1A5 and SLC38A2 overexpression in human cells, respectively, and found that only SLC38A2, but not SLC1A5, resulted in a cancer‐like metabolic profile, where the intracellular concentrations of essential amino acids and lactate were significantly increased as quantified by nuclear magnetic resonance spectroscopy. Finally, we analyzed the 5‐year survival rates in a large pan‐cancer cohort and found that the SLC1A5^hi/SLC38A2^lo group did not relate to a poor survival rate, whereas the SLC1A5^lo/SLC38A2^hi group significantly aggravated the lethality. Intriguingly, the SLC1A5^hi/SLC38A2^hi group resulted in an even worse prognosis, suggesting a cooperative effect between SLC1A5 and SCL38A2. Our data suggest that SLC38A2 plays a dominant role in reprogramming the cancer‐like metabolism and promoting the cancer progression, whereas SLC1A5 may augment this effect when co‐overexpressed with SLC38A2. We propose a model to explain the relationship between SLC1A5, SLC38A2 and SCL7A5, and discuss their impact on glutaminolysis and mTOR signaling.

更新日期：2020-11-17

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