MEK activation suppresses CPT11-induced apoptosis in rat intestinal epithelial cells through a COX-2-dependent mechanism.
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.
Horikawa
Youhei
Y
Department of Gastroenterology/Internal Medicine, Akita University School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.
Otaka
Michiro
M
Komatsu
Koga
K
Jin
Mario
M
Odashima
Masaru
M
Wada
Isao
I
Matsuhashi
Tamotsu
T
Ohba
Reina
R
Oyake
Jinko
J
Hatakeyama
Natsumi
N
Dubois
Raymond N
RN
Watanabe
Sumio
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002470:Cell Survival; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007414:Intestinal Neoplasms / Q000378:metabolism* / Q000473:pathology; D000077146:Irinotecan; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051381:Rats; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D000077146:Irinotecan; D051546:Cyclooxygenase 2; D020929:Mitogen-Activated Protein Kinase Kinases; D002166:Camptothecin