國家衛生研究院 NHRI:Item 3990099045/8176
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    題名: Discovery of selective inhibitors of Glutaminase-2, which inhibit mTORC1, activate autophagy and inhibit proliferation in cancer cells
    作者: Lee, YZ;Yang, CW;Chang, HY;Hsu, HY;Chen, IS;Chang, HS;Lee, CH;Lee, JC;Kumar, CR;Qiu, YQ;Chao, YS;Lee, SJ
    貢獻者: Institute of Biotechnology and Pharmaceutical Research
    摘要: Glutaminase, which converts glutamine to glutamate, is involved in Warburg effect in cancer cells. Two human glutaminase genes have been identified, GLS (GLS1) and GLS2. Two alternative transcripts arise from each glutaminase gene: first, the kidney isoform (KGA) and glutaminase C (GAC) for GLS; and, second, the liver isoform (LGA) and glutaminase B (GAB) for GLS2. While GLS1 is considered as a cancer therapeutic target, the potential role of GLS2 in cancer remains unclear. Here, we discovered a series of alkyl benzoquinones that preferentially inhibit glutaminase B isoform (GAB, GLS2) rather than the kidney isoform of glutaminase (KGA, GLS1). We identified amino acid residues in an allosteric binding pocket responsible for the selectivity. Treatment with the alkyl benzoquinones decreased intracellular glutaminase activity and glutamate levels. GLS2 inhibition by either alkyl benzoquinones or GLS2 siRNA reduced carcinoma cell proliferation and anchorage-independent colony formation, and induced autophagy via AMPK mediated mTORC1 inhibition. Our findings demonstrate amino acid sequences for selective inhibition of glutaminase isozymes and validate GLS2 as a potential anti-cancer target.
    日期: 2014-08
    關聯: Oncotarget. 2014 Aug;5(15):6087-6101.
    Link to: http://dx.doi.org/10.18632/oncotarget.2173
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000347919500020
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84906270661
    顯示於類別:[李秀珠] 期刊論文
    [李靜琪] 期刊論文
    [趙宇生(2002-2013)] 期刊論文

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