MEK activation suppresses CPT11-induced apoptosis in rat intestinal epithelial cells through a COX-2-dependent mechanism

Youhei Horikawa, Michiro Otaka, Koga Komatsu, Mario Jin, Masaru Odashima, Isao Wada, Tamotsu Matsuhashi, Reina Ohba, Jinko Oyake, Natsumi Hatakeyama, Raymond N. DuBois, Sumio Watanabe

    Research output: Contribution to journalArticlepeer-review

    5 Scopus citations

    Abstract

    Resistance to chemotherapeutic agents is one of the distinct features of cancer cells. We evaluate the role of activated MEK-ERK signaling in Camptotecin/irinotecan (CPT-11)-induced cell death using constitutively activated MEK1-transfected normal rat intestinal epithelial cells (IEC-caMEK cells). A CPT-11-induced inhibitory concentration of 50% was determined by WST assay. Apoptosis was evaluated by DNA staining and fragmented DNA analysis. Protein expressions were analyzed by western blotting. We also examined the role of cyclooxygenase-2 in the cell systems. IEC-caMEK cells possessed survival advantages compared to control cells. Apoptosis was remarkably suppressed in IEC-caMEK cells. Western blot analysis revealed increased expression of Bcl-2, Bcl-xL, Mcl-1, and COX-2 and decreased expression of Bak in IEC-caMEK cells. The COX-2 selective inhibitor ameliorated the antiapoptotic nature of IEC-caMEK cells. MEK activation suppressed CPT-11-induced apoptosis in IEC-caMEK cells via a COX-2- dependent mechanism. Therefore, MEK-ERK signaling may contribute to the drug-resistant nature of cancer cells.

    Original languageEnglish (US)
    Pages (from-to)2757-2765
    Number of pages9
    JournalDigestive Diseases and Sciences
    Volume52
    Issue number10
    DOIs
    StatePublished - Oct 1 2007

    Keywords

    • Apoptosis
    • COX-2
    • Chemotherapeutic agents
    • MEK-ERK signaling

    ASJC Scopus subject areas

    • Physiology
    • Gastroenterology

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