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

V W Y Lui1, E Y L Wong, K Ho

  • 1Cancer 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.

Oncogene
|November 9, 2010
PubMed

Insights

c-Met tyrosine kinase inhibitors (TKIs) reduce nasopharyngeal cancer growth by downregulating TIGAR and depleting NADPH. This reveals a new therapeutic pathway targeting the tyrosine kinase/TIGAR/NADPH cascade in cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • c-Met is a key therapeutic target in various cancers.
  • Nasopharyngeal cancer (NPC) is an invasive head and neck cancer prevalent in Asia.
  • Understanding c-Met's mechanism in NPC is crucial for targeted therapy.

Purpose of the Study:

  • To elucidate the mechanism by which c-Met tyrosine kinase inhibition affects NPC growth and invasion.
  • To identify downstream targets of c-Met inhibition in NPC.
  • To explore the therapeutic potential of targeting the c-Met pathway in NPC.

Main Methods:

  • Utilized c-Met tyrosine kinase inhibitors (TKIs), AM7 and SU11274, in NPC cell lines.
  • Assessed c-Met phosphorylation, cell growth, invasion, TP53-induced Glycolysis and Apoptosis Regulator (TIGAR) expression, and intracellular NADPH levels.
  • Investigated the effect of TIGAR overexpression on c-Met TKI-induced inhibition.

Main Results:

  • c-Met TKIs significantly downregulated c-Met phosphorylation, NPC cell growth, and invasion.
  • Inhibition of c-Met led to decreased TIGAR expression and subsequent depletion of intracellular NADPH.
  • Overexpression of TIGAR counteracted the inhibitory effects of c-Met kinase inhibition, confirming TIGAR's role.

Conclusions:

  • c-Met kinase inhibition impacts NPC via downregulation of TIGAR and subsequent NADPH depletion.
  • This study reveals a novel tyrosine kinase/TIGAR/NADPH signaling cascade.
  • Targeting this cascade presents a potential therapeutic strategy for human cancers, including NPC.

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