Cyclooxygenase-2 (COX-2) negatively regulates expression of epidermal growth factor receptor and causes resistance to gefitinib in COX-2-overexpressing cancer cells

Young-Mee Kim, Soo Yeon Park, Hongryull Pyo

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Overexpression of cyclooxygenase-2 (COX-2) and epidermal growthfactor receptor (EGFR) has been detected in many types of cancer. Although COX-2 and EGFR are closely related to each other, the exact mechanism of COX-2 in tumors has not been well understood. In this study, we investigated the relationship between COX-2 and EGFR in cancer cells. Using two cell lines stably overexpressing COX-2 (HCT-116-COX-2 and H460-COX-2) and a stable line of COX-2 knockdown MOR-P cells, we analyzed patterns of COX-2 and EGFR expression. To observe the effects of COX-2 on EGFR expression and activity, we did comparative analyses after treatment withvarious drugs (EGF, celecoxib, prostaglandin E2, gefitinib, Ro-31-8425, PD98059, and SP600125) in HCT-116-Mock versus HCT-116-COX-2 cells and H460-Mock versus H460-COX-2 cells. Overexpression of COX-2 specifically down-regulated EGFR expression at the level of transcription. COX-2-overexpressing cells have a decreased sensitivity to gefitinib. COX-2 induced activation of extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) but suppressed Akt activation. JNK inhibition by SP600125, a specific JNK inhibitor, resulted in restoration of EGFR levels in COX-2-overexpressing cells, whereas ERK inhibition by PD98059 did not. Overexpressed COX-2 negatively regulates EGFR expression via JNK activation, leading to gefitinib resistance. COX-2 may also regulate ERK activity independently of EGFR. Therefore, resistance of COX-2-overexpressing cells to gefitinib may be due to decreased expression of EGFR by JNK activation and EGFR-independent elevation of ERK activity by COX-2. The ability of COX-2 to inhibit EGFR expression and gefitinib effects may have significance in clinical cancer therapy.

Original languageEnglish (US)
Pages (from-to)1367-1377
Number of pages11
JournalMolecular Cancer Research
Volume7
Issue number8
DOIs
StatePublished - Aug 1 2009

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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