NSAIDs activate PTEN and other phosphatases in human colon cancer cells: novel mechanism for chemopreventive action of NSAIDs.
Studies on chemoprevention of colorectal cancer have generated increasing interest. The mechanisms involved in NSAIDs chemopreventive action are not fully elucidated. In this study, we examined in human colon cancer cells the effect of indomethacin and NS-398 (a pre-clinical selective COX-2 inhibitor) on expression of 96 genes of the EGF/PDGF signaling pathways essential for cell proliferation, migration, and survival. We found that indomethacin and NS-398 treatment significantly upregulated expression of the tumor suppressor gene, PTEN, the MAP kinase phosphatase-3, MKP-3, and the protein tyrosine phosphatase, SHP2. Additionally, NS-398 treatment increased expression of apoptotic genes such as BAD, STAT1, and CASP3. These results suggest that as a consequence of increased expression of phosphatases such as PTEN and the resulting dephosphorylation of kinases, NSAIDs can negatively regulate the EGF/PDGF pathways in colon cancer cells-a novel mechanism for NSAIDs' chemopreventive actions.
Chu
Eric C
EC
Department of Medicine, Division of Gastroenterology, VA Long Beach Healthcare System and University of California, Irvine, USA.
Chai
Jianyuan
J
Tarnawski
Andrzej S
AS
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D018938:Caco-2 Cells; D018890:Chemoprevention / Q000379:methods; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology*; D009578:Nitrobenzenes / Q000494:pharmacology*; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D014018:Tissue Distribution / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; D009578:Nitrobenzenes; D010982:Platelet-Derived Growth Factor; D013449:Sulfonamides; D025521:Tumor Suppressor Proteins; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D004815:Epidermal Growth Factor; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D007213:Indomethacin