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Enhanced BCAT1 activity and BCAA metabolism promotes RhoC activity in cancer progression

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机构: [1]Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, School of Basic Medical Sciences, Cancer Institutes, Key Laboratory of Breast Cancer in Shanghai, Shanghai Key Laboratory of Radiation Oncology, The Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College, Fudan University, Shanghai, China [2]Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China [3]Department of Pathology, Fudan University Shanghai Cancer Center, Institute of Pathology, Fudan University, Shanghai, China [4]Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China [5]Institutes of Biomedical Sciences, Fudan University, Shanghai, China [6]Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China [7]State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China [8]State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China [9]Present address: Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Increased expression of branched-chain amino acid transaminase 1 or 2 (BCAT1 and BCAT2) has been associated with aggressive phenotypes of different cancers. Here we identify a gain of function of BCAT1 glutamic acid to alanine mutation at codon 61 (BCAT1E61A) enriched around 2.8% in clinical gastric cancer samples. We found that BCAT1E61A confers higher enzymatic activity to boost branched-chain amino acid (BCAA) catabolism, accelerate cell growth and motility and contribute to tumor development. BCAT1 directly interacts with RhoC, leading to elevation of RhoC activity. Notably, the BCAA-derived metabolite, branched-chain α-keto acid directly binds to the small GTPase protein RhoC and promotes its activity. BCAT1 knockout-suppressed cell motility could be rescued by expressing BCAT1E61A or adding branched-chain α-keto acid. We also identified that candesartan acts as an inhibitor of BCAT1E61A, thus repressing RhoC activity and cancer cell motility in vitro and preventing peritoneal metastasis in vivo. Our study reveals a link between BCAA metabolism and cell motility and proliferation through regulating RhoC activation, with potential therapeutic implications for cancers.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.

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出版当年[2022]版:
大类 | 1 区 医学
小类 | 1 区 内分泌学与代谢
最新[2023]版:
大类 | 1 区 医学
小类 | 1 区 内分泌学与代谢
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出版当年[2021]版:
Q1 ENDOCRINOLOGY & METABOLISM
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Q1 ENDOCRINOLOGY & METABOLISM

影响因子: 最新[2023版] 最新五年平均 出版当年[2021版] 出版当年五年平均 出版前一年[2020版] 出版后一年[2022版]

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第一作者机构: [1]Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, School of Basic Medical Sciences, Cancer Institutes, Key Laboratory of Breast Cancer in Shanghai, Shanghai Key Laboratory of Radiation Oncology, The Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College, Fudan University, Shanghai, China [2]Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
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通讯机构: [1]Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, School of Basic Medical Sciences, Cancer Institutes, Key Laboratory of Breast Cancer in Shanghai, Shanghai Key Laboratory of Radiation Oncology, The Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College, Fudan University, Shanghai, China [2]Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China [7]State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China
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