Inhibition of c-Met downregulates TIGAR expression and reduces NADPH production leading to cell death
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摘要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
著者Lui VWY, Wong EYL, Ho K, Ng PKS, Lau CPY, Tsui SKW, Tsang CM, Tsao SW, Cheng SH, Ng MHL, Ng YK, Lam EKY, Hong B, Lo KW, Mok TSK, Chan ATC, Mills GB
期刊名稱Oncogene
出版年份2011
月份3
日期1
卷號30
期次9
出版社Nature Publishing Group: Open Access Hybrid Model Option B
頁次1127 - 1134
國際標準期刊號0950-9232
電子國際標準期刊號1476-5594
語言英式英語
關鍵詞c-Met tyrosine kinase inhibitor; NADPH; TIGAR
Web of Science 學科類別Biochemistry & Molecular Biology; BIOCHEMISTRY & MOLECULAR BIOLOGY; Cell Biology; CELL BIOLOGY; Genetics & Heredity; GENETICS & HEREDITY; Oncology; ONCOLOGY

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