title: Inhibition of activator protein 1 activity and neoplastic transformation by aspirin.
abstract: Aspirin, along with its analgesic-antipyretic uses, is now also being considered for prevention of cardiovascular disease, cancer, and treatment of human immunodeficiency virus infection. Although many of aspirin's pharmacological actions are related to its ability to inhibit prostaglandin biosynthesis, some of its beneficial therapeutic effects are not completely understood. Transcription factor activator protein 1 (AP-1) is critical for the induction of neoplastic transformation and induction of multiple genes involved in inflammation and infection. We have used the JB6 mouse epidermal cell lines, a system that has been used extensively as an in vitro model for the study of tumor promotion and anti-tumor promotion, to study the anti-carcinogenesis effect of aspirin at the molecular level. Aspirin and aspirin-like salicylates inhibited the activation of AP-1 in the same dose range as seen for the inhibition of tumor promoter-induced transformation. The inhibition of AP-1 and tumor promoter-induced transformation in JB6 cells occurs through a prostaglandin independent- and an Erk1- or Erk2-independent pathway. The mechanism of AP-1 and transformation inhibition in this cell culture model may involve the elevation of H+ concentration. The inhibition effects on the activation of AP-1 activity by aspirin and aspirin-like salicylates may further explain the anti-carcinogenesis mechanism of action of these drugs.
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.zgdong@wolf.co.net
authors.forename: Z
authors.initials: Z
authors.lastname: Dong
authors.forename: C
authors.initials: C
authors.lastname: Huang
authors.forename: R E
authors.initials: RE
authors.lastname: Brown
authors.forename: W Y
authors.initials: WY
authors.lastname: Ma
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002273:Carcinogens / Q000494:pharmacology; D002448:Cell Adhesion; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004054:Diethylstilbestrol / Q000494:pharmacology; D016758:Genes, jun; D011905:Genes, ras; D006863:Hydrogen-Ion Concentration; D007213:Indomethacin / Q000494:pharmacology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D010766:Phosphorylation; D012980:Sodium Salicylate / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D002273:Carcinogens; D016861:Cyclooxygenase Inhibitors; D018808:Transcription Factor AP-1; D004054:Diethylstilbestrol; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate; D001241:Aspirin; D012980:Sodium Salicylate; D007213:Indomethacin