title: Hepatocytes display a compensatory survival response against cadmium toxicity by a mechanism mediated by EGFR and Src.
abstract: Although the liver is a cadmium-target organ, hepatocyte response involved in its toxicity is not yet elucidated. A link between this heavy metal treatment and Stat3 signaling pathways was examined in primary mouse hepatocytes. We provided evidence of a novel link among NADPH oxidase and Stat3 signaling, mediated by Src, EGFR, and Erk1/2. Cadmium activates NADPH oxidase. ROS produced by this oxidase activates Src, enable that in turn, transactivates EGFR that activates Stat3 in tyrosine, allowing its dimerization. Also, ROS from NADPH oxidase favors ERK1/2 activation that phosphorylates Stat3 in serine, resulting in a compensatory or adaptive survival response such as production of metallothionein-II in short Cd exposure times. However, after 12h CdCl2 treatment, cell viability diminished in 50%, accompanied by a drastic decrease of metallothionein-II production, and an increase in p53 activation and the pro-apoptotic protein Bax.
authors: Departamento Ciencias de la Salud, División de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Mexico.
authors: K
authors: K
authors: Martínez Flores
authors: B C
authors: BC
authors: Uribe Marín
authors: V
authors: V
authors: Souza Arroyo
authors: L
authors: L
authors: Bucio Ortiz
authors: A
authors: A
authors: López Reyes
authors: L E
authors: LE
authors: Gómez-Quiroz
authors: E
authors: E
authors: Rojas del Castillo
authors: M C
authors: MC
authors: Gutiérrez Ruiz
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002104:Cadmium / Q000633:toxicity*; D002470:Cell Survival; D002478:Cells, Cultured; D004785:Environmental Pollutants / Q000633:toxicity*; D066246:ErbB Receptors / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008668:Metallothionein / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D004785:Environmental Pollutants; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D002104:Cadmium; D008668:Metallothionein; D019255:NADPH Oxidases; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D019061:src-Family Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3