MEK Activation Suppresses CPT11-Induced Apoptosis in Rat Intestinal Epithelial Cells Through a COX-2-Dependent Mechanism |
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Authors: | 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 |
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Affiliation: | (1) Department of Gastroenterology/Internal Medicine, Akita University School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan;(2) Department of Medicine, Cell/Developmental Biology and Cancer Biology, Vanderbilt-Ingram Cancer Center, 694 PRB, Nashville, Tennessee 37232, USA |
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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. |
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Keywords: | MEK-ERK signaling Chemotherapeutic agents Apoptosis COX-2 |
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