Epigallocatechin gallate (EGCG), a major component of green tea, is a dual phosphoinositide-3-kinase/mTOR inhibitor |
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Authors: | Van Aller Glenn S Carson Jeff D Tang Wei Peng Hao Zhao Lin Copeland Robert A Tummino Peter J Luo Lusong |
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Institution: | aDepartment of Cancer Research, GlaxoSmithKline, Collegeville, PA 19426, USA;bDiscovery Biology, BioDuro, No. 29 Life Science Park Road, Changping, Beijing, China |
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Abstract: | The PI3K signaling pathway is activated in a broad spectrum of human cancers, either directly by genetic mutation or indirectly via activation of receptor tyrosine kinases or inactivation of the PTEN tumor suppressor. The key nodes of this pathway have emerged as important therapeutic targets for the treatment of cancer. In this study, we show that (−)-epigallocatechin-3-gallate (EGCG), a major component of green tea, is an ATP-competitive inhibitor of both phosphoinositide-3-kinase (PI3K) and mammalian target of rapamycin (mTOR) with Ki values of 380 and 320 nM respectively. The potency of EGCG against PI3K and mTOR is within physiologically relevant concentrations. In addition, EGCG inhibits cell proliferation and AKT phosphorylation at Ser473 in MDA-MB-231 and A549 cells. Molecular docking studies show that EGCG binds well to the PI3K kinase domain active site, agreeing with the finding that EGCG competes for ATP binding. Our results suggest another important molecular mechanism for the anticancer activities of EGCG. |
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Keywords: | Abbreviations: EGCG (&minus )-epigallocatechin-3-gallate PI3K phosphoinositide-3-kinase mTOR mammalian target of rapamycin PI(3 4 5)P3 phosphatidylinositol-3 4 5-triphosphate ATP adenosine 5&prime -triphosphate mTORC2 mammalian target of rapamycin complex 2 FRAP1 FK506 binding protein 12-rapamycin associated protein PDK1 phosphoinositide-dependent kinase 1 |
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