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Deletion of cyclooxygenase-2 inhibits K-ras-induced lung carcinogenesis

Yong Pan1, Yan Jiang1, Lin Tan1

  • 1Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Oncotarget
|October 10, 2015
PubMed

Insights

Cyclooxygenase-2 (COX-2) deficiency suppresses K-ras-induced lung cancer by reducing tumor growth and cell proliferation. This suggests COX-2 and prostaglandin E2 (PGE2) are potential targets for lung cancer prevention.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • K-ras mutations are common drivers in lung cancer.
  • Cyclooxygenase-2 (COX-2) is implicated in various cancers, but its specific role in K-ras-induced lung carcinogenesis requires elucidation.
  • Prostaglandin E2 (PGE2) is a key mediator in inflammation and cancer progression.

Purpose of the Study:

  • To investigate the role of COX-2 in the development of K-ras-driven lung cancer.
  • To determine the impact of COX-2 deficiency on tumor formation, growth, and molecular pathways in a mouse model of lung cancer.

Main Methods:

  • Generated genetically engineered mouse models: K-rasLA1 (G12D) mice crossed with COX-2-homozygous knockout mice (K-ras/COX-2(-/-)) and control K-ras mice.
  • Assessed tumor incidence, size, and hyperplasia.
  • Quantified levels of prostaglandin E2 (PGE2) and its metabolite 13,14-dihydro-15-keto-PGE2 in lung tumors.
  • Measured tumor cell proliferation rates and protein expression of MEK and p-Erk1/2.
  • Utilized A549 non-small cell lung cancer cells to validate findings in vitro.

Main Results:

  • K-ras/COX-2(-/-) mice exhibited significantly fewer and smaller lung adenocarcinomas and reduced bronchioalveolar hyperplasias compared to K-ras mice.
  • Lung tumors in K-ras/COX-2(-/-) mice showed lower PGE2 levels and higher levels of the PGE2 metabolite 13,14-dihydro-15-keto-PGE2.
  • Tumor cell proliferation, MEK, and p-Erk1/2 protein levels were significantly reduced in K-ras/COX-2(-/-) mice.
  • In vitro studies confirmed that COX-2 knockdown in A549 cells reduced colony formation, PGE2 synthesis, and ERK phosphorylation.

Conclusions:

  • COX-2 deletion significantly represses K-ras-induced lung tumorigenesis.
  • The mechanism involves reduced tumor cell proliferation, decreased PGE2 production, and increased 13,14-dihydro-15-keto-PGE2, potentially mediated by the MAPK pathway.
  • COX-2 and its product PGE2 represent promising therapeutic targets for lung cancer prevention and treatment.
Keywords:
COX-2K-ras oncogeneMAP kinaselung adenocarcinomamouse

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