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LKB1/STK11 suppresses cyclooxygenase-2 induction and cellular invasion through PEA3 in lung cancer

Sunil Upadhyay1, Chunyan Liu, Aditi Chatterjee

  • 1Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA.

Cancer Research
|August 17, 2006
PubMed

Insights

Inactivation of LKB1 (a tumor suppressor) in lung cancer stabilizes PEA3, promoting cell invasion. Restoring wild-type LKB1 reduces PEA3, inhibiting cancer progression and epithelial-mesenchymal transition.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • LKB1 (serine/threonine kinase) is frequently mutated in lung cancer.
  • PEA3 is a transcriptional factor implicated in cancer progression.

Purpose of the Study:

  • To investigate the interaction between PEA3 and LKB1 in lung cancer.
  • To elucidate the role of this interaction in lung cancer cell invasion and epithelial-mesenchymal transition.

Main Methods:

  • Co-immunoprecipitation to study protein interactions.
  • Western blotting to assess protein expression and degradation.
  • Quantitative real-time PCR for gene expression analysis.
  • Matrigel invasion assays to evaluate cell invasiveness.
  • RNA interference to inhibit PEA3 expression.

Main Results:

  • LKB1 directly interacts with PEA3 via its ETS and kinase domains, respectively.
  • LKB1 phosphorylates PEA3, targeting it for proteasomal degradation.
  • LKB1 mutations stabilize PEA3, leading to increased cyclooxygenase-2 expression.
  • PEA3 stabilization in mutant LKB1 cells correlates with enhanced invasion and epithelial-mesenchymal transition.
  • Inhibition of PEA3 significantly reduces invasion in LKB1-mutant lung cancer cells.

Conclusions:

  • LKB1 inactivation in lung cancer leads to PEA3 stabilization.
  • Stabilized PEA3 promotes lung cancer cell invasion and epithelial-mesenchymal transition.
  • Targeting the LKB1-PEA3 axis may offer therapeutic strategies for lung cancer.

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