Cyclooxygenase-2 up-regulates ataxia telangiectasia and Rad3 related through extracellular signal-regulated kinase activation

Mee Kim Young, Jung Lee Eun, Soo Yeon Park, Ho Cho Kwan, Young Kim Joo, Hongryull Pyo

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Cyclooxygenase-2 (COX-2) overexpression caused prolonged G2 arrest after exposure to ionizing radiation (IR) in our previous study. We were therefore interested in investigating the function of COX-2 in the G2 checkpoint pathway. Interestingly, we found that cells in which COX-2 is overexpressed showed up-regulated ataxia telangiectasia and Rad3 related (ATR) expression compared with control cells. In this study, we investigated the mechanism of ATR up-regulation by COX-2 and tested our hypothesis that COX-2 - induced extracellular signal-regulated kinase (ERK) activation mediates up-regulation of ATR by COX-2. To investigate the relationship between COX-2 and ATR, we used two stable COX-2 - overexpressing cancer cell lines (HCT116 - COX-2 and H460 - COX-2), a COX-2 knockdown A549 lung cancer cell line (AS), and an ATR knockdown HCT116 cell line. Cells were treated with various drugs [celecoxib, prostaglandin E2 (PGE2), PD98059, U0126, and hydroxyurea] and were then analyzed using reverse transcription-PCR, confocal microscopy, Western blotting, and clonogenic assay. COX-2 - overexpressing cells were shown to have increased ERK phosphorylation and ATR expression compared with control cells, whereas AS cells were shown to have decreased levels of phospho-ERK and ATR. In addition, exogenously administered PGE2 increased ERK phosphorylation. Inhibition of ERK phosphorylation decreased ATR expression in both HCT116 - COX-2 and A549 cells. HCT116 - COX-2 cells were resistant to IR or hydroxyurea compared with HCT116-Mock cells, whereas administration of ATR shRNA showed the opposite effect. COX-2 stimulates ERK phosphorylation via PGE2. This COX-2 - induced ERK activation seems to increase ATR expression and activity in endogenous COX-2 - overexpressing cancer cells as well as in COX-2 - overexpressing stable cell lines.

Original languageEnglish (US)
Pages (from-to)1158-1168
Number of pages11
JournalMolecular Cancer Research
Volume7
Issue number7
DOIs
StatePublished - Jul 1 2009
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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