title: Arsenite maintains germinative state in cultured human epidermal cells.
abstract: Arsenic is a well-known carcinogen for human skin, but its mechanism of action and proximal macromolecular targets remain to be elucidated. In the present study, low micromolar concentrations of sodium arsenite maintained the proliferative potential of epidermal keratinocytes, decreasing their exit from the germinative compartment under conditions that promote differentiation of untreated cells. This effect was observed in suspension and in post-confluent surface cultures as measured by colony-forming ability and by proportion of rapidly adhering colony-forming cells. Arsenite-treated cultures exhibited elevated levels of beta1-integrin and beta-catenin, two proteins enriched in cells with high proliferative potential. Levels of phosphorylated (inactive) glycogen synthase kinase 3beta were higher in the treated cultures, likely accounting for the increased levels of transcriptionally available beta-catenin. These findings suggest that arsenic could have co-carcinogenic and tumor co-promoting activities in the epidermis as a result of increasing the population and persistence of germinative cells targeted by tumor initiators and promoters. These findings also identify a critical signal transduction pathway meriting further exploration in pursuit of this phenomenon.
authors.affiliation: Department of Environmental Toxicology, University of California, One Shields Avenue, Davis, CA 95616-8588, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Patterson
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Reznikova
authors.forename: Marjorie A
authors.initials: MA
authors.lastname: Phillips
authors.forename: Robert H
authors.initials: RH
authors.lastname: Rice
mesh_terms: D018053:Arsenites / Q000633:toxicity*; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D000078404:Epidermal Cells; D004817:Epidermis / Q000187:drug effects* / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018053:Arsenites; D011518:Proto-Oncogene Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; C015001:arsenite