Inhibition of c-Met downregulates TIGAR expression and reduces NADPH production leading to cell death.
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.
Cancer Signaling Laboratory, Department of Clinical Oncology, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer, Chinese University of Hong Kong, Hong Kong, China.
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Lui
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Wong
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Ng
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Lau
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Tsui
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Tsang
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Tsao
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Cheng
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Ng
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Lam
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Hong
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Mok
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Chan
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Mills
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D015536:Down-Regulation; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D009249:NADP / Q000096:biosynthesis*; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010744:Phosphoric Monoester Hydrolases; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011744:Pyrimidinones / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology*
C478479:((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide); C558303:5-(3-fluoro-4-((6-(methyloxy)-7-((3-(4-morpholinyl)propyl)oxy)-4-quinolinyl)oxy)phenyl)-3-methyl-2-(phenylmethyl)-4(3H)pyrimidinone; D051017:Apoptosis Regulatory Proteins; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011744:Pyrimidinones; D011804:Quinolines; D013449:Sulfonamides; D009249:NADP; D019859:Proto-Oncogene Proteins c-met; D010744:Phosphoric Monoester Hydrolases; C512708:TIGAR protein, human