title: Copper ability to induce premature senescence in human fibroblasts.
abstract: Human diploid fibroblasts (HDFs) exposed to subcytotoxic concentrations of oxidative or stressful agents, such as hydrogen peroxide, tert-butylhydroperoxide, or ethanol, undergo stress-induced premature senescence (SIPS). This condition is characterized by the appearance of replicative senescence biomarkers such as irreversible growth arrest, increase in senescence-associated β-galactosidase (SA β-gal) activity, altered cell morphology, and overexpression of several senescence-associated genes. Copper is an essential trace element known to accumulate with ageing and to be involved in the pathogenesis of some age-related disorders. Past studies using either yeast or human cellular models of ageing provided evidence in favor of the role of intracellular copper as a longevity modulator. In the present study, copper ability to cause the appearance of senescent features in HDFs was assessed. WI-38 fibroblasts exposed to a subcytotoxic concentration of copper sulfate presented inhibition of cell proliferation, cell enlargement, increased SA β-gal activity, and mRNA overexpression of several senescence-associated genes such as p21, apolipoprotein J (ApoJ), fibronectin, transforming growth factor β-1 (TGF β1), insulin growth factor binding protein 3, and heme oxygenase 1. Western blotting results confirmed enhanced intracellular p21, ApoJ, and TGF β1 in copper-treated cells. Thus, similar to other SIPS-inducing agents, HDF exposure to subcytotoxic concentration of copper results in premature senescence. Further studies will unravel molecular mechanisms and the biological meaning of copper-associated senescence and lead to a better understanding of copper-related disorder establishment and progression.
authors.affiliation: Faculty of Nutrition and Food Sciences, University of Porto, Rua Dr. Roberto Frias, Oporto, Portugal. lmatos@fcna.up.pt
authors.forename: Liliana
authors.initials: L
authors.lastname: Matos
authors.forename: Alexandra
authors.initials: A
authors.lastname: Gouveia
authors.forename: Henrique
authors.initials: H
authors.lastname: Almeida
mesh_terms: D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects* / Q000502:physiology; D051152:Clusterin / Q000235:genetics / Q000378:metabolism*; D019327:Copper Sulfate / Q000494:pharmacology*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006801:Humans; D018384:Oxidative Stress / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D012016:Reference Values; D012494:Sampling Studies; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D001616:beta-Galactosidase / Q000187:drug effects / Q000378:metabolism
chemical_list: D051152:Clusterin; D012333:RNA, Messenger; D001616:beta-Galactosidase; D019327:Copper Sulfate