title: Induction of apoptosis and cell cycle arrest by NS398 in oral squamous cell carcinoma cells via downregulation of E2 promoter-binding factor-1.
abstract: Overexpression of cyclooxygenase-2 (COX-2) plays an important role in development and progression of different human cancers, but the underlying molecular mechanisms remain to be defined. Tissue specimens of normal oral epithelia (n=9), dysplasia (n=38), and oral squamous cell carcinoma (SCC, n=54) were immunohistochemically analyzed for COX-2 and E2F-1 expression. A human oral SCC cell line, Tca8113, was used to assess NS398 antitumor activity. PGE2 levels were measured by using radioimmunoassay, and COX-2, pRb, and E2F-1 proteins were determined by Western blot assay. We found expression of COX-2 and E2F-1 proteins was significantly increased in both oral dysplasia and SCC compared to the normal epithelium. Increased COX-2 expression was associated with E2F-1 expression in both oral dysplasia and SCC. NS398 treatment reduced viability of Tca8113 cells in a dose- and time-dependent manner. NS398 suppressed PGE2 levels, a product of COX-2 enzyme, in the tumor cells. The reduced cell viability is due to induction of apoptosis by NS398, which activates caspase-3, but does not inhibit bcl-2. NS398 also induced tumor cell arrest at G1 phase of the cell cycle and inhibited expression of COX-2, pRb and E2F-1 proteins. This study provides evidence that E2F-1 and COX-2 are overexpressed in oral cancer, and further supports suppression of COX-2 in control of oral cancer.
authors.affiliation: Department of Oral and Maxillofacial Surgery, School of Stomatology, Nanjing Medical University, Nanjing, P.R. China.
authors.forename: Yifei
authors.initials: Y
authors.lastname: Du
authors.forename: Shuangyue
authors.initials: S
authors.lastname: Zhang
authors.forename: Zilu
authors.initials: Z
authors.lastname: Wang
authors.forename: Weina
authors.initials: W
authors.lastname: Zhou
authors.forename: Mingliang
authors.initials: M
authors.lastname: Luan
authors.forename: Xiaohan
authors.initials: X
authors.lastname: Yang
authors.forename: Ning
authors.initials: N
authors.lastname: Chen
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D007124:Immunoenzyme Techniques; D009061:Mouth Mucosa; D009062:Mouth Neoplasms / Q000378:metabolism / Q000473:pathology*; D009578:Nitrobenzenes / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D016861:Cyclooxygenase Inhibitors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D053148:Caspase 3; D015232:Dinoprostone