title: Oncogenic H-Ras, FK228, and exogenous H2O2 cooperatively activated the ERK pathway in selective induction of human urinary bladder cancer J82 cell death.
abstract: More than 35% of human urinary bladder cancers involve oncogenic H-Ras activation. The goal of this study was to investigate the role of the ERK pathway in mediating apoptotic signals induced by oncogenic H-Ras, FK228 treatment, and exogenous H(2) O(2) treatment to increase Nox-1 elevation, leading to production of intracellular reactive oxygen species (ROS) for inducing apoptosis in human bladder cancer J82 cells. Our study revealed that FK228 combined with exogenous H(2)O(2) cooperatively induced activation of Mek1/2 and Erk1/2 to increase Nox-1 elevation, intracellular ROS production, caspase activation, and cell death. Expression of oncogenic H-Ras significantly increased these FK228- and exogenous H(2)O(2)-induced effects. Oncogenic H-Ras-increased cell susceptibility to FK228 could be alternately achieved by additional treatment with exogenous H(2)O(2). Hence, combined use of FK228 with ROS-generating agents may apply to therapeutic strategies to preferentially kill malignant cells with or without oncogenic H-Ras activation.
authors.affiliation: Department of Comparative Medicine, Anticancer Molecular Oncology Laboratory, College of Veterinary Medicine, The University of Tennessee, Knoxville, Tennessee 37996, USA.
authors.forename: Shambhunath
authors.initials: S
authors.lastname: Choudhary
authors.forename: Kwo-Kwang Abraham
authors.initials: KK
authors.lastname: Wang
authors.forename: Hwa-Chain Robert
authors.initials: HC
authors.lastname: Wang
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D003131:Combined Modality Therapy; D047630:Depsipeptides / Q000494:pharmacology*; D004789:Enzyme Activation; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*
chemical_list: D000903:Antibiotics, Antineoplastic; D047630:Depsipeptides; D016877:Oxidants; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; C087123:romidepsin; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases; C402799:NOX1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020169:Caspases; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)