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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis
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Apoptosis Regulatory Proteins
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Survival
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Down-Regulation
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Humans
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Indoles / pharmacology*
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Intracellular Signaling Peptides and Proteins / genetics*
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NADP / biosynthesis*
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Nasopharyngeal Neoplasms / drug therapy
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Nasopharyngeal Neoplasms / metabolism*
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Nasopharyngeal Neoplasms / pathology
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Phosphoric Monoester Hydrolases
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Phosphorylation
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Piperazines / pharmacology*
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Protein Kinase Inhibitors / pharmacology*
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Proto-Oncogene Proteins c-met / antagonists & inhibitors*
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Proto-Oncogene Proteins c-met / genetics
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Proto-Oncogene Proteins c-met / metabolism
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Pyrimidinones / pharmacology*
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Quinolines / pharmacology*
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Sulfonamides / pharmacology*
Substances
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((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)
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5-(3-fluoro-4-((6-(methyloxy)-7-((3-(4-morpholinyl)propyl)oxy)-4-quinolinyl)oxy)phenyl)-3-methyl-2-(phenylmethyl)-4(3H)pyrimidinone
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Apoptosis Regulatory Proteins
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Indoles
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Intracellular Signaling Peptides and Proteins
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Piperazines
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Protein Kinase Inhibitors
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Pyrimidinones
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Quinolines
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Sulfonamides
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NADP
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Proto-Oncogene Proteins c-met
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Phosphoric Monoester Hydrolases
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TIGAR protein, human