期刊
ONCOGENE
卷 30, 期 9, 页码 1127-1134出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2010.490
关键词
c-Met tyrosine kinase inhibitor; TIGAR; NADPH
资金
- Research Grant Council, Hong Kong Government [471607]
- Head and Neck SPORE [P50 CA097007]
- CCSG [P30CA16672]
- [2006.1.027]
- [2007.1.025]
- [2009.1.012]
c-Met represents an important emerging therapeutic target in cancer. In this study, we demonstrate the mechanism by which c-Met tyrosine kinase inhibition inhibits tumor growth in a highly invasive Asian-prevalent head and neck cancer, nasopharyngeal cancer (NPC). c-Met tyrosine kinase inhibitors (TKIs; AM7 and c-Met TKI tool compound SU11274) downregulated c-Met phosphorylation, resulting in marked inhibition of NPC cell growth and invasion. Strikingly, inhibition of c-Met resulted in significant downregulation of TP53-induced Glycolysis and Apoptosis Regulator (TIGAR) and subsequent depletion of intracellular NADPH. Importantly, overexpression of TIGAR ameliorated the effects of c-Met kinase inhibition, confirming the importance of TIGAR downregulation in the growth inhibitory activity of c-Met TKI. The effects of c-Met inhibition on TIGAR and NADPH levels were observed with two different c-Met TKIs (AM7 and SU11274) and with multiple cell lines. As NADPH provides a crucial reducing power required for cell survival and proliferation, our findings reveal a novel mechanistic action of c-Met TKI, which may represent a key effect of c-Met kinase inhibition. Our data provide the first evidence linking c-Met, TIGAR and NADPH regulation in human cancer cells suggesting that inhibition of a tyrosine kinase/TIGAR/NADPH cascade may have therapeutic applicability in human cancers. Oncogene (2011) 30, 1127-1134; doi:10.1038/onc.2010.490; published online 8 November 2010
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