title: Negative feedback regulation of phosphatidylinositol 3-kinase/Akt pathway by over-expressed cyclooxygenase-2 in human epidermal cancer cells.
abstract: While enhanced expression of cyclooxygenase (COX)-2 has been observed in human skin epidermal cancer, the mechanisms underlying COX-2 expression have not been completely elucidated. Recently, a role for the phosphatidylinositol-3 (PI3) kinase pathway in COX-2 expression has attracted attention. We investigated COX-2 expression, PI3 kinase activity, and the phosphorylation level of Akt, a downstream effector of PI3 kinase, in the human skin cancer cell line HSC-5. Compared to the nontumorigenic keratinocyte HaCaT, in HSC-5 cells, COX-2 protein expression and PI3 kinase activity were increased. The PI3 kinase inhibitor LY294002 reduced COX-2 expression in HSC-5 cells and, contrary to our expectation, the phosphorylation of Akt was significantly decreased. The expression of Bcl-2, which is regulated by Akt, was reduced, and apoptosis was induced in HSC-5 cells compared to HaCaT cells. COX-2 inhibitor NS398 up-regulated Akt phosphorylation. These results imply that constitutively over-expressed COX-2 down-regulates the Akt phosphorylation through a negative feedback mechanism.
authors.affiliation: Department of Dermatology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Takeda
authors.forename: Takuro
authors.initials: T
authors.lastname: Kanekura
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Kanzaki
mesh_terms: D017209:Apoptosis / Q000502:physiology; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D002470:Cell Survival; D051546:Cyclooxygenase 2; D053938:DNA Fragmentation; D004273:DNA, Neoplasm; D015536:Down-Regulation; D000078404:Epidermal Cells; D005246:Feedback; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D015603:Keratinocytes / Q000502:physiology; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D007527:Isoenzymes; D008565:Membrane Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D019869:Phosphatidylinositol 3-Kinases