title: PTEN regulates apoptotic cell death through PI3-K/Akt/GSK3β signaling pathway in DMH induced early colon carcinogenesis in rat.
abstract: Phosphatidylinositol 3-kinase (PI3-K) and Akt (protein kinase B), are both essential signaling molecules that are up-regulated in various cancers. Here, we examined the molecular mechanisms by which PI3-K and Akt expression are regulated by glycogen synthase kinase-3β (GSK-3β) and the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in the early stages of experimental colon carcinogenesis. 1,2-dimethylhydrazine (DMH) was utilized for the induction of colon cancer while piroxicam, a traditional non-steroidal anti-inflammatory drug and c-phycocyanin, a biliprotein from Spirulina platensis (cyanobacterium) as the chemopreventive agents. Western blotting and immunofluorescence results indicated that the expression of PI3-K and Akt was promoted in the DMH group while least apoptosis was detected in this group as analyzed by Hoechst 33342-propidium iodide co-staining. DMH group further detected lower GSK-3β and PTEN expression as compared to other groups. Piroxicam and c-phycocyanin treatment resulted significant apoptotic cell death while showing low PI3-K and Akt expressions. Mitochondrial membrane potential (ΔΨ(M)) alterations (examined by JC-1 and rhodamine 123 labeling of colonocytes) and fluorescence intensity measurement of ROS level, were also analyzed showing the raised ΔΨ(M) while reduced ROS levels in DMH group, however piroxicam and c-phycocyanin treatment resulted in falling of ΔΨ(M) although both stimulated the ROS production as analyzed by flow cytometry. The present study thus identified that piroxicam, a traditional NSAID and c-phycocyanin, a newly discovered COX-2 selective inhibitor, constitute remarkable chemopreventive targets in mediating apoptosis in the DMH induced early rat colon carcinogenesis via regulating PI3-K/Akt/GSK-3β/PTEN signaling pathways. Further, a combination of the two drugs provides a better therapeutic option, than the monotherapy regimen.
authors.affiliation: Department of Biophysics, Panjab University, Chandigarh, 160014, India.
authors.forename: Manpreet Kaur
authors.initials: MK
authors.lastname: Saini
authors.forename: Sankar Nath
authors.initials: SN
authors.lastname: Sanyal
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017209:Apoptosis; D002273:Carcinogens / Q000633:toxicity; D002277:Carcinoma / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000187:drug effects; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004127:Dimethylhydrazines / Q000633:toxicity; D004359:Drug Therapy, Combination; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D058539:Phosphatidylinositol 3-Kinase / Q000096:biosynthesis*; D010798:Phycocyanin / Q000494:pharmacology; D010894:Piroxicam / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002273:Carcinogens; D052246:Cyclooxygenase 2 Inhibitors; D004127:Dimethylhydrazines; D017382:Reactive Oxygen Species; D010798:Phycocyanin; D010894:Piroxicam; D058539:Phosphatidylinositol 3-Kinase; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D051059:PTEN Phosphohydrolase; C487216:Pten protein, rat