期刊
ONCOTARGET
卷 5, 期 15, 页码 6087-6101出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.2173
关键词
AMPK; Autophagy; Glutaminase; mTOR; Raptor; ULK1
资金
- Ministry of Economic Affairs, R.O.C. [101-EC-17-A-02-04-1099, 102-EC-17-A-02-04-1099, 103-EC-17-A-22-1099]
- National Science Council of Taiwan [NSC 102-2628-B-400-002-MY3]
- National Health Research Institutes, Taiwan, R.O.C.
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据