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Inhibition of c-Met downregulates TIGAR expression and reduces NADPH production leading to cell death

Oncogene volume 30, pages 1127–1134 (2011)Cite this article

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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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Author notes

  1. V W Y Lui, E Y L Wong, K Ho and C P Y Lau: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Clinical Oncology, Cancer Signaling Laboratory, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer, Chinese University of Hong Kong, Hong Kong, China

    V W Y Lui, E Y L Wong, K Ho, C P Y Lau, E K Y Lam, B Hong, T S K Mok & A T C Chan

  2. School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China

    P K S Ng & S K W Tsui

  3. Department of Anatomy, University of Hong Kong, Hong Kong, China

    C-M Tsang & S-W Tsao

  4. Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Hong Kong, China

    S H Cheng, M H L Ng & K W Lo

  5. Department of Surgery, Chinese University of Hong Kong, Hong Kong, China

    Y K Ng

  6. Department of Systems Biology, MD Anderson Cancer Center, University of Texas at Houston, TX, USA

    G B Mills

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  1. V W Y Lui
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Correspondence to A T C Chan.

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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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