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甲硫氨酸协调顺铂耐药膀胱癌微环境中的代谢脆弱性。

Methionine orchestrates the metabolism vulnerability in cisplatin resistant bladder cancer microenvironment.

机构信息

Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.

Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China.

出版信息

Cell Death Dis. 2023 Aug 15;14(8):525. doi: 10.1038/s41419-023-06050-1.

DOI:10.1038/s41419-023-06050-1
PMID:37582769
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10427658/
Abstract

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.

摘要

顺铂耐药的膀胱癌细胞的代谢脆弱性仍有待发现，我们应用整合的多组学分析来阐明膀胱癌微环境中的代谢相关调控机制。代谢组学和蛋白质组学的整合多组学分析表明，MAT2A 调节蛋氨酸代谢有助于膀胱癌细胞的顺铂耐药。我们进一步验证了 MAT2A 和癌症干细胞标志物上调，circARHGAP10 通过调节顺铂耐药膀胱癌细胞中 MAT2A 蛋白稳定性而下调。circARHGAP10 与 MAT2A 和 TRIM25 形成复合物，通过泛素-蛋白酶体途径加速 MAT2A 的降解。通过过表达 circARHGAP10 和限制蛋氨酸摄取来敲低 MAT2A 足以在免疫缺陷模型中体内克服顺铂耐药，但在免疫功能正常的模型中则不然。肿瘤浸润的 CD8 T 细胞在低蛋氨酸肿瘤中表现出衰竭表型。SLC7A6 在膀胱癌中的高表达与 CD8 的表达呈负相关。MAT2A 和 SLC7A6 的协同抑制可以在体内免疫功能正常的模型中克服顺铂耐药。顺铂耐药的膀胱癌细胞依赖于蛋氨酸来生存和干细胞更新。circARHGAP10/TRIM25/MAT2A 调节途径在顺铂耐药的膀胱癌细胞中起着重要作用，而 circARHGAP10 和 SLC7A6 应被评估为顺铂耐药的膀胱癌的治疗靶点之一。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b252/10427658/6b32f1c18251/41419_2023_6050_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b252/10427658/19c62766b901/41419_2023_6050_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b252/10427658/9e3113cc2b53/41419_2023_6050_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b252/10427658/1feb18cfa117/41419_2023_6050_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b252/10427658/654e54b39c47/41419_2023_6050_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b252/10427658/61437dec5ec8/41419_2023_6050_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b252/10427658/635f28384f3f/41419_2023_6050_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b252/10427658/8a8e1de10694/41419_2023_6050_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b252/10427658/6b32f1c18251/41419_2023_6050_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b252/10427658/19c62766b901/41419_2023_6050_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b252/10427658/9e3113cc2b53/41419_2023_6050_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b252/10427658/1feb18cfa117/41419_2023_6050_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b252/10427658/654e54b39c47/41419_2023_6050_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b252/10427658/61437dec5ec8/41419_2023_6050_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b252/10427658/635f28384f3f/41419_2023_6050_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b252/10427658/8a8e1de10694/41419_2023_6050_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b252/10427658/6b32f1c18251/41419_2023_6050_Fig8_HTML.jpg

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