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

• Published in: Digestive diseases and sciences 2007-10, Vol.52 (10), p.2757-2765
• Main Authors: HORIKAWA, Youhei, OTAKA, Michiro, DUBOIS, Raymond N, WATANABE, Sumio, KOMATSU, Koga, JIN, Mario, ODASHIMA, Masaru, WADA, Isao, MATSUHASHI, Tamotsu, OHBA, Reina, OYAKE, Jinko, HATAKEYAMA, Natsumi
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Biological and medical sciences; Blotting, Western; Bones, joints and connective tissue. Antiinflammatory agents; Camptothecin - analogs & derivatives; Camptothecin - pharmacology; Cell Survival; Cyclooxygenase 2 - drug effects; Cyclooxygenase 2 - metabolism; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial Cells - pathology; Intestinal Mucosa - drug effects; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Intestinal Neoplasms - metabolism; Intestinal Neoplasms - pathology; Medical sciences; Mitogen-Activated Protein Kinase Kinases - drug effects; Mitogen-Activated Protein Kinase Kinases - metabolism; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; Pharmacology. Drug treatments; Rats; Signal Transduction; Tumor Cells, Cultured
• ISSN: 0163-2116; 1573-2568
• DOI: 10.1007/s10620-007-9798-0

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.