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 T P53-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.
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Acknowledgements
We would like to thank Amgen, Inc. (USA) for the kind provision of the novel c-Met tyrosine kinase inhibitor, AM7. This study was supported by Research Grant Council, Hong Kong Government (471607) and Direct Grants for Research (2006.1.027; 2007.1.025; 2009.1.012) to VWYL. GBM is supported by Head and Neck SPORE P50 CA097007 and CCSG grant P30CA16672.
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Lui, V., Wong, E., Ho, K. et al. Inhibition of c-Met downregulates TIGAR expression and reduces NADPH production leading to cell death. Oncogene 30, 1127–1134 (2011). https://doi.org/10.1038/onc.2010.490
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DOI: https://doi.org/10.1038/onc.2010.490
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