蛋氨酸在顺铂耐药膀胱癌微环境中协调代谢易感性。
Methionine orchestrates the metabolism vulnerability in cisplatin resistant bladder cancer microenvironment.
发表日期：2023 Aug 15
作者：
Chen Yang, Yuxi Ou, Quan Zhou, Yingchun Liang, Weijian Li, Yiling Chen, Wensun Chen, Siqi Wu, Yifan Chen, Xiyu Dai, Xinan Chen, Tian Chen, Shengming Jin, Yufei Liu, Limin Zhang, Shenghua Liu, Yun Hu, Lujia Zou, Shanhua Mao, Haowen Jiang
来源：
Stem Cell Research & Therapy
摘要：
BCa细胞对顺铂耐药的代谢脆弱性仍然未被发现，我们应用综合的多组学分析揭示了膀胱癌（BCa）微环境中与代谢相关的调控机制。代谢组学和蛋白组学的综合分析揭示了MAT2A调节的甲硫氨酸代谢对BCa细胞顺铂耐药性的贡献。我们进一步验证了MAT2A和癌干细胞标志物的上调以及circARHGAP10在顺铂耐药性BCa细胞中的下调，通过调节MAT2A蛋白的稳定性。circARHGAP10与MAT2A和TRIM25形成复合物，通过ubiquitin-蛋白酶体途径加速MAT2A的降解。通过过表达circARHGAP10和限制甲硫氨酸摄取来敲低MAT2A，在体免疫缺陷模型中足以克服顺铂耐药性，但在体免疫能力模型中不能。肿瘤浸润的CD8+ T细胞表现出疲劳表型，低甲硫氨酸肿瘤中与CD8表达负相关的SLC7A6高表达。MAT2A和SLC7A6的协同抑制可以在体免疫能力模型中克服顺铂耐药性。顺铂耐药BCa细胞依赖甲硫氨酸生存和干细胞更新。circARHGAP10/TRIM25/MAT2A调控途径在顺铂耐药BCa细胞中起着重要作用，而circARHGAP10和SLC7A6应被评估为顺铂耐药BCa的治疗靶点之一。© 2023. 作者。
Metabolism vulnerability of cisplatin resistance in BCa cells remains to be discovered, which we applied integrated multi-omics analysis to elucidate the metabolism related regulation mechanism in bladder cancer (BCa) microenvironment. Integrated multi-omics analysis of metabolomics and proteomics revealed that MAT2A regulated methionine metabolism contributes to cisplatin resistance in BCa cells. We further validated MAT2A and cancer stem cell markers were up-regulated and circARHGAP10 was down-regulated through the regulation of MAT2A protein stability in cisplatin resistant BCa cells. circARHGAP10 formed a complex with MAT2A and TRIM25 to accelerate the degradation of MAT2A through ubiquitin-proteasome pathway. Knockdown of MAT2A through overexpression of circARHGAP10 and restriction of methionine up-take was sufficient to overcome cisplatin resistance in vivo in immuno-deficiency model but not in immuno-competent model. Tumor-infiltrating CD8+ T cells characterized an exhausted phenotype in tumors with low methionine. High expression of SLC7A6 in BCa negatively correlated with expression of CD8. Synergistic inhibition of MAT2A and SLC7A6 could overcome cisplatin resistance in immuno-competent model in vivo. Cisplatin resistant BCa cells rely on methionine for survival and stem cell renewal. circARHGAP10/TRIM25/MAT2A regulation pathway plays an important role in cisplatin resistant BCa cells while circARHGAP10 and SLC7A6 should be evaluated as one of the therapeutic target of cisplatin resistant BCa.© 2023. The Author(s).