title: Cyclooxygenase-2 expression is up-regulated by 2-aminobiphenyl in a ROS and MAPK-dependent signaling pathway in a bladder cancer cell line.
abstract: Overexposure to biphenyl amine compounds, which are found in smoke and azo-dyes, is linked to the occurrence of bladder cancer. However, the molecular mechanisms of biphenyl amine compound-induced bladder cancer are still unclear. Many studies have demonstrated that overexpression of cyclooxygenase-2 (COX-2) in neoplastic lesions is associated with carcinogenesis. In this study, we have demonstrated that 2-aminobiphenyl (2-ABP) up-regulated the expression of COX-2 in a dose- and time-dependent manner in TSGH-8301 bladder cancer cells. This 2-ABP-induced COX-2 expression was attenuated by ROS scavenger NAC and NADPH oxidase inhibitors apocynin and DPI. The p22phox subunit of NADPH oxidase, but not p67, and Nox2 was up-regulated by 2-ABP. Knocking down p22phox by siRNA significantly reduced 2-ABP-induced COX-2 expression. Furthermore, 2-ABP also activated the ERK/JNK-AP1 pathways, and this effect was also abolished by NADPH oxidase inhibitors. Blocking the ERK/JNK-AP1 signaling pathways by pharmacological inhibitors attenuated 2-ABP-induced COX-2 expression. Overexpression of the upstream ERK activator MEK1 significantly and consistently increased 2-ABP-mediated COX-2 expression. Transfection of a dominant negative c-Jun mutant, TAM-67, blocked 2-ABP-mediated COX-2 expression, demonstrating that c-Jun was responsible for the transcriptional activation. Taken together, these results demonstrate that 2-ABP induces the carcinogenic factor COX-2 and that this induction is mediated through NADPH oxidase-derived ROS-dependent JNK/ERK-AP-1 pathways.
authors.affiliation: Department of Biotechnology, National Kaohsiung Normal University, No. 62, Shenjhong Road, Yanchao District, Kaohsiung City 82444, Taiwan.
authors.forename: Chien-Cheng
authors.initials: CC
authors.lastname: Chen
authors.forename: Yu-Yang
authors.initials: YY
authors.lastname: Cheng
authors.forename: Ssu-Ching
authors.initials: SC
authors.lastname: Chen
authors.forename: Yen-Fan
authors.initials: YF
authors.lastname: Tuan
authors.forename: Yun-Ju
authors.initials: YJ
authors.lastname: Chen
authors.forename: Chien-Yen
authors.initials: CY
authors.lastname: Chen
authors.forename: Lei-Chin
authors.initials: LC
authors.lastname: Chen
mesh_terms: D000611:Aminobiphenyl Compounds / Q000633:toxicity*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006202:Hair Dyes; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D019255:NADPH Oxidases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014028:Tobacco Smoke Pollution; D015854:Up-Regulation; D001749:Urinary Bladder Neoplasms
chemical_list: D000611:Aminobiphenyl Compounds; D006202:Hair Dyes; D017382:Reactive Oxygen Species; D014028:Tobacco Smoke Pollution; C014970:2-aminodiphenyl; D051546:Cyclooxygenase 2; D019255:NADPH Oxidases