title: Cr(VI) induces premature senescence through ROS-mediated p53 pathway in L-02 hepatocytes.
abstract: Hexavalent Chromium [Cr(VI)], which can be found of various uses in industries such as metallurgy and textile dying, can cause a number of human disease including inflammation and cancer. Unlike previous research that focused on Cr(VI)-induced oxidative damage and apoptosis, this study placed emphasis on premature senescence that can be induced by low-dose and long-term Cr(VI) exposure. We found Cr(VI) induced premature senescence in L-02 hepatocytes, as confirmed by increase in senescence associated-β-galactosidase (SA-β-Gal) activity. Cr(VI) stabilized p53 through phosphorylation at Ser15 and increased expression of p53-transcriptional target p21. Mechanism study revealed Cr(VI) targeted and inhibited mitochondrial respiratory chain complex (MRCC) I and II to enhance reactive oxygen species (ROS) production. By applying antioxidant Trolox, we also confirmed that ROS mediated p53 activation. A tetracycline-inducible lentiviral expression system containing shRNA to p53 was used to knockout p53. We found p53 could inhibit pro-survival genes B-cell lymphoma-2 (Bcl-2), myeloid leukemia-1 (Mcl-1) and S phase related cell cycle proteins cyclin-dependent kinase 2 (CDK2), Cyclin E to induce premature senescence, and the functional role of ROS in Cr(VI)-induced premature senescence is depend on p53. The results suggest that Cr(VI) has a role in premature senescence by promoting ROS-dependent p53 activation in L-02 hepatocytes.
authors.affiliation: Department of Health Toxicology, Xiangya School of Public Health, Central South University, Changsha 410078, P.R. China.
authors.forename: Yujing
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Health Toxicology, Xiangya School of Public Health, Central South University, Changsha 410078, P.R. China.
authors.forename: Yiyuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Health Toxicology, Xiangya School of Public Health, Central South University, Changsha 410078, P.R. China.
authors.forename: Caigao
authors.initials: C
authors.lastname: Zhong
authors.affiliation: Department of Health Toxicology, Xiangya School of Public Health, Central South University, Changsha 410078, P.R. China.
authors.forename: Fang
authors.initials: F
authors.lastname: Xiao
mesh_terms: D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D002857:Chromium / Q000633:toxicity*; D042967:Electron Transport Complex I / Q000378:metabolism; D042963:Electron Transport Complex II / Q000378:metabolism; D022781:Hepatocytes; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D002857:Chromium; C074702:chromium hexavalent ion; D042963:Electron Transport Complex II; D042967:Electron Transport Complex I