PTEN regulates apoptotic cell death through PI3-K/Akt/GSK3尾 signaling pathway in DMH induced early colon carcinogenesis in rat

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• 作者：Manpreet Kaur Saini ; Sankar Nath Sanyal ; ^{sanyalpu@gmail.com}
• 关键词：Apoptosis ; PI3-K ; GSK-3尾 ; Akt ; PTEN ; 螖唯M
• 刊名：Experimental and Molecular Pathology
• 出版年：2012
• 期刊代码：291_00144800
• 类别：med
• 出版时间：August, 2012
• 卷：93
• 期：1
• 页码：135-146
• 文件大小：2621 K

摘要

Phosphatidylinositol 3-kinase (PI3-K) and Akt (protein kinase B), are both essential signaling molecules that are up鈥恟egulated in various cancers. Here, we examined the molecular mechanisms by which PI3-K and Akt expression are regulated by glycogen synthase kinase鈥?尾 (GSK-3尾) 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-3尾 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 (螖唯_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 螖唯_M while reduced ROS levels in DMH group, however piroxicam and c-phycocyanin treatment resulted in falling of 螖唯_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-3尾/PTEN signaling pathways. Further, a combination of the two drugs provides a better therapeutic option, than the monotherapy regimen.