國家衛生研究院 NHRI:Item 3990099045/8176

NHRI > Institute of Biotechnology and Pharmaceutical Research > Shiow-Ju Lee > Periodical Articles > Item 3990099045/8176

Please use this identifier to cite or link to this item: http://ir.nhri.org.tw/handle/3990099045/8176

Title:	Discovery of selective inhibitors of Glutaminase-2, which inhibit mTORC1, activate autophagy and inhibit proliferation in cancer cells
Authors:	Lee, YZ;Yang, CW;Chang, HY;Hsu, HY;Chen, IS;Chang, HS;Lee, CH;Lee, JC;Kumar, CR;Qiu, YQ;Chao, YS;Lee, SJ
Contributors:	Institute of Biotechnology and Pharmaceutical Research
Abstract:	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.
Date:	2014-08
Relation:	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
Appears in Collections:	[Shiow-Ju Lee] Periodical Articles [Jinq-Chyi Lee] Periodical Articles [Yu-Sheng Chao(2002-2013)] Periodical Articles

Files in This Item:

File	Description	Size	Format
PUB25026281.pdf		1459Kb	Adobe PDF	665	View/Open

Loading...