1. Academic Validation
  2. Hexavalent chromium triggers hepatocytes premature senescence via the GATA4/NF-κB signaling pathway mediated by the DNA damage response

Hexavalent chromium triggers hepatocytes premature senescence via the GATA4/NF-κB signaling pathway mediated by the DNA damage response

  • Ecotoxicol Environ Saf. 2022 Jul 1;239:113645. doi: 10.1016/j.ecoenv.2022.113645.
Yu Ma 1 Siwen Li 2 Shuzi Ye 3 Die Hu 3 Lai Wei 3 Fang Xiao 4
Affiliations

Affiliations

  • 1 Xiangya School of Public Health, Central South University, Changsha 410078, PR China. Electronic address: [email protected].
  • 2 Xiangya School of Public Health, Central South University, Changsha 410078, PR China. Electronic address: [email protected].
  • 3 Xiangya School of Public Health, Central South University, Changsha 410078, PR China.
  • 4 Xiangya School of Public Health, Central South University, Changsha 410078, PR China. Electronic address: [email protected].
Abstract

Hexavalent chromium [Cr(VI)] is a proven toxin, carcinogen and environmental pollutant. Oral intake of Cr(VI) has been shown to lead to an increasing incidence of primary hepatic carcinoma in the population. Cellular senescence is thought to be a natural barrier to malignant transformation of cells, but senescence-associated secretory phenotype (SASP) is secreted and regulated by senescent cells links cellular senescence to malignant transformation in a dynamic way. In the present research, we demonstrated novel mechanisms of premature hepatocytes senescence induced by Cr(VI). Continuous Cr(VI) stimulation led to DNA damaged in hepatocytes, and DNA damage response (DDR) signals were transmitted by ataxia telangiectasia-mutated gene (ATM)/ataxia telangiectasia and Rad-3-related protein (ATR), resulting in zinc finger transcription factor GATA4 escaping p62-mediated selective Autophagy, thereby regulating nuclear factor kappa-B (NF-κB) to induce premature senescence in hepatocytes. In contrast to the classical senescence pathway p53-p21WAF1 /CIP1 and Rb/p16INK4a, GATA4 can directly regulate the secretion of SASP during premature senescence. The results will provide valuable clues for targeted prevention and further individualized treatment of Cr(VI)-associated cancers.

Keywords

Hexavalent chromium [Cr(VI)]; Nuclear factor kappa-B (NF-κB); Premature senescence; Senescence-associated secretion phenotype (SASP); Zinc finger transcription factor GATA4.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15520
    99.83%, ATM/ATR Inhibitor