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- Title
Inhibition of c-Met downregulates TIGAR expression and reduces NADPH production leading to cell death.
- Authors
Lui, V W Y; Wong, E Y L; Ho, K; Ng, P K S; Lau, C P Y; Tsui, S K W; Tsang, C-M; Tsao, S-W; Cheng, S H; Ng, M H L; Ng, Y K; Lam, E K Y; Hong, B; Lo, K W; Mok, T S K; Chan, A T C; Mills, G B
- Abstract
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.
- Subjects
GLYCOLYSIS; APOPTOSIS; PROTEIN-tyrosine kinase inhibitors; TUMOR growth; HEAD &; neck cancer; CELL lines
- Publication
Oncogene, 2011, Vol 30, Issue 9, p1127
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/onc.2010.490