Cyclooxygenase-2 overexpression inhibits death receptor 5 expression and confers resistance to tumor necrosis factor-related apoptosis-inducng ligand-induced apoptosis in human colon cancer cells

Ximing Tang, Yun Jie Sun, Elizabeth Half, M. Tien Kuo, Frank Sinicrope

Research output: Contribution to journalArticle

122 Scopus citations

Abstract

The inducible cyclooxygenase-2 (COX-2) gene regulates prostaglandin biosynthesis, is up-regulated in colorectal cancers, and can influence apoptotic susceptibility. We determined whether forced COX-2 expression modulates apoptosis induction by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of tumor necrosis factor ligand family, and examined determinants of the apoptotic pathway, including membrane death receptors (DR-4 and DR-5). HCT-15 colon cancer cells lacking endogenous COX-2 proteins were stably transfected with the COX-2 cDNA and incubated with TRAIL. Forced COX-2 expression significantly attenuated TRAIL-induced apoptosis and was associated with transcriptional repression of DR-5 and up-regulation of Bcl-2. COX-2 transfectants showed reduced DR-5 mRNA and protein expression as well as reduced caspase-8, caspase-3, and caspase-9 activation relative to parental cells. Sulindac sulfide treatment restored DR-5 expression and, when combined with TRAIL, reduced cell viability to a greater extent than did either drug alone. In summary, modulation of DR-5 and Bcl-2 levels by COX-2 attenuates TRAIL-induced apoptosis and represents a novel mechanism of intrinsic drug resistance in human colon cancer cells.

Original languageEnglish (US)
Pages (from-to)4903-4908
Number of pages6
JournalCancer research
Volume62
Issue number17
StatePublished - Sep 1 2002

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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