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PTEN regulates apoptotic cell death through PI3-K/Akt/GSK3beta signaling pathway in DMH induced early colon carcinogenesis in rat.

Authors: Saini, MK  Sanyal, SN 
Citation: Saini MK and Sanyal SN, Exp Mol Pathol. 2012 Aug;93(1):135-46. doi: 10.1016/j.yexmp.2012.04.019. Epub 2012 Apr 25.
Pubmed: (View Article at PubMed) PMID:22561258
DOI: Full-text: DOI:10.1016/j.yexmp.2012.04.019

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-3beta (GSK-3beta) 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-3beta 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 (DeltaPsi(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 DeltaPsi(M) while reduced ROS levels in DMH group, however piroxicam and c-phycocyanin treatment resulted in falling of DeltaPsi(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-3beta/PTEN signaling pathways. Further, a combination of the two drugs provides a better therapeutic option, than the monotherapy regimen.

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CRRD Object Information
CRRD ID: 10045586
Created: 2015-06-12
Species: All species
Last Modified: 2015-06-12
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.