title: PI3-kinase/Wnt association mediates COX-2/PGE(2) pathway to inhibit apoptosis in early stages of colon carcinogenesis: chemoprevention by diclofenac.
abstract: In addition to having anti-inflammatory properties, non-steroidal anti-inflammatory drugs (NSAIDs) inhibit neoplastic cell proliferation by inducing apoptosis. Inhibition of cyclooxygenase-2 (COX-2) seemed to be the principal target of NSAIDs, as it is overexpressed in several cancers and catalyzes the synthesis of prostaglandin E₂ (PGE₂), the critical pro-inflammatory molecule. A major role for phosphatidylinositol-3 kinase (PI3-kinase) pathway activation in human tumors has been more recently established. The present study explored the role of PI3-kinase and Wnt molecular pathways in COX-2 and PGE₂ production as well as NSAIDs' chemopreventive effect in colon cancer. 1,2-dimethylhydrazine (DMH) was used for experimental colon cancer model in rat and diclofenac as the preferential COX-2 selective chemopreventive agent. Expression of caspase-3 and caspase-9 was checked in the colonic tissue by immunofluorescence. A decrease was seen in their expressions, indicative of inhibition of apoptosis in the present model. COX-2 mRNA expression as well as PGE₂ levels was elevated after DMH treatment; however, COX-1 mRNA expression was unaltered as seen by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. DMH also activated PI3-kinase, Akt, Wnt, and β-catenin expressions but reduced the glycogen synthase kinase-3β (GSK-3β) levels. Co-administration of diclofenac with DMH increased the mRNA expression of GSK-3β while inactivating PI3-kinase, Akt, Wnt, and β-catenin. The study suggests that activation of PI3-kinase and Wnt signaling is associated with COX-2/PGE₂ production and in turn inhibition of apoptosis in colon cancer, while diclofenac targeted these pathways to restore apoptosis in the present system.
authors.affiliation: Department of Biophysics, Panjab University, Chandigarh 160 014, India.
authors.forename: Jasmeet
authors.initials: J
authors.lastname: Kaur
authors.forename: Sankar Nath
authors.initials: SN
authors.lastname: Sanyal
mesh_terms: D019813:1,2-Dimethylhydrazine / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004008:Diclofenac / Q000494:pharmacology* / Q000627:therapeutic use; D015232:Dinoprostone / Q000378:metabolism*; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D051153:Wnt Proteins; D051176:beta Catenin; D004008:Diclofenac; D051546:Cyclooxygenase 2; D019869:Phosphatidylinositol 3-Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3; D053453:Caspase 9; D019813:1,2-Dimethylhydrazine; D015232:Dinoprostone