title: p66Shc signaling is involved in stress responses elicited by anthracycline treatment of rat cardiomyoblasts.
abstract: The adaptor protein p66Shc modulates cellular redox status integrating oxidative stress with mitochondrial stress responses. Upon oxidative stress, p66Shc is translocated to mitochondria or mitochondria-associated membranes in a multi-step process, resulting in locally increased reactive oxygen species production. This signaling pathway is believed to be important in the context of drug-induced organ toxicity. The use of anthracyclines as anticancer agents is limited due to a dose-dependent and cumulative toxicity resulting in cardiomyopathy. Treatment with the anthracycline doxorubicin (DOX) results in a dose-dependent and cumulative cardiotoxicity which is mediated, at least in part, by increased oxidative stress. In the present study, we investigated for the first time whether p66Shc signaling is activated during DOX treatment of the rat cardiomyoblast H9c2 cell line. We further tested whether the transcriptional factor FoxO3a, which activates target genes responsible for apoptosis and cell cycle arrest, is also involved in p66Shc-dependent redox signaling pathway. Our results suggest that DOX treatment induces p66Shc protein up-regulation specifically in nuclear fractions. Increased nuclear expression of FoxO3a was also detected in H9c2 cells after DOX treatment. Treatment with the antioxidant and protein kinase C (PKC-β) inhibitor hispidin decreased DOX-induced activation of caspase 9 and p66Shc alterations. Taking together, we hypothesize that p66Shc signaling is involved in the activation of stress/toxicity responses elicited by the treatment of H9c2 cells with DOX. Hence, the selective inhibition of this redox pathway may be a promising therapeutic approach to circumvent DOX cardiotoxicity.
authors: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, UC Biotech Building, Lot 8A, Biocant Park, 3060-197, Cantanhede, Portugal.
authors: Susana F
authors: SF
authors: Sampaio
authors: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, UC Biotech Building, Lot 8A, Biocant Park, 3060-197, Cantanhede, Portugal.|Department of Life Sciences, University of Coimbra, Coimbra, Portugal.
authors: Ana F
authors: AF
authors: Branco
authors: Department of Biochemistry, Nencki Institute of Experimental Biology, Warsaw, Poland.
authors: Aleksandra
authors: A
authors: Wojtala
authors: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, UC Biotech Building, Lot 8A, Biocant Park, 3060-197, Cantanhede, Portugal.|Department of Morphology and Cellular Biology, University of Oviedo, Oviedo, Spain.
authors: Ignacio
authors: I
authors: Vega-Naredo
authors: Department of Biochemistry, Nencki Institute of Experimental Biology, Warsaw, Poland.
authors: Mariusz R
authors: MR
authors: Wieckowski
authors: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, UC Biotech Building, Lot 8A, Biocant Park, 3060-197, Cantanhede, Portugal. pauloliv@ci.uc.pt.
authors: Paulo J
authors: PJ
authors: Oliveira
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D066126:Cardiotoxicity; D018929:Cell Culture Techniques; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000633:toxicity*; D000071316:Forkhead Box Protein O3 / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D055785:Gene Knockdown Techniques; D032386:Myoblasts, Cardiac / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D021381:Protein Transport; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; C499515:FOXO3 protein, rat; D000071316:Forkhead Box Protein O3; C528035:Shc1 protein, rat; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D004317:Doxorubicin
keywords: Cardiotoxicity; Doxorubicin; FoxO3a; H9c2 rat cardiomyoblasts; p66Shc