Copper exposure induces hepatic G0/G1 cell-cycle arrest through suppressing the Ras/PI3K/Akt signaling pathway in mice

Huan Liu; Huidan Deng; Zhijie Jian; Hengmin Cui; Hongrui Guo; Jing Fang; Zhicai Zuo; Junliang Deng; Yinglun Li; Xun Wang; Ling Zhao; Yanqiu Zhu

doi:10.1016/j.ecoenv.2021.112518

Copper exposure induces hepatic G0/G1 cell-cycle arrest through suppressing the Ras/PI3K/Akt signaling pathway in mice

Ecotoxicol Environ Saf. 2021 Oct 1:222:112518. doi: 10.1016/j.ecoenv.2021.112518. Epub 2021 Jul 14.

Authors

Huan Liu¹, Huidan Deng², Zhijie Jian¹, Hengmin Cui³, Hongrui Guo⁴, Jing Fang², Zhicai Zuo², Junliang Deng², Yinglun Li², Xun Wang², Ling Zhao², Yanqiu Zhu¹

Affiliations

¹ College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China.
² College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China; Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China.
³ College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China; Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China; Key Laboratory of Agricultural information engineering of Sichuan Province, Sichuan Agriculture University, Yaan, Sichuan 625014, China. Electronic address: chm2020@sicau.edu.cn.
⁴ College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China; Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China. Electronic address: guohongrui@sicau.edu.cn.

PMID: 34271501
DOI: 10.1016/j.ecoenv.2021.112518

Abstract

Copper (Cu), as a common chemical contaminant in environment, is known to be toxic at high concentrations. The current research demonstrates the effects of copper upon hepatocyte cell-cycle progression (CCP) in mice. Institute of cancer research (ICR) mice (n = 240) at an age of four weeks were divided randomly into groups treated with different doses of Cu (0, 4, 8, and 16 mg/kg) for 21 and 42 days. Results showed that high Cu exposure caused hepatocellular G0/G1 cell-cycle arrest (CCA) and reduced cell proportion in the G2/M phase. G0/G1 CCA occurred with down-regulation (p < 0.05) of Ras, p-PI3K (Tyr458), p-Akt (Thr308), p-forkhead box O3 (FOXO3A) (Ser253), p-glycogen synthase kinase 3-β (GSK3-β) (Ser9), murine double minute 2 (MDM2) protein, and mRNA expression levels, and up-regulation (p < 0.05) of PTEN, p-p53 (Ser15), p27, p21 protein, and mRNA expression levels, which subsequently suppressed (p < 0.05) the protein and mRNA expression levels of CDK2/4 and cyclin E/D. These results indicate that Cu exposure suppresses the Ras/PI3K/Akt signaling pathway to reduce the level of CDK2/4 and cyclin E/D, which are essential for the G1-S transition, and finally causes hepatocytes G0/G1 CCA.

Keywords: Copper; G0/G1 cell-cycle arrest; Liver; Ras/PI3K/Akt signaling pathway.

MeSH terms

Animals
Cell Line, Tumor
Cell Proliferation
Copper / toxicity
G1 Phase Cell Cycle Checkpoints
Glycogen Synthase Kinase 3
Mice
Phosphatidylinositol 3-Kinases* / genetics
Phosphatidylinositol 3-Kinases* / metabolism
Proto-Oncogene Proteins c-akt* / genetics
Proto-Oncogene Proteins c-akt* / metabolism
Signal Transduction

Substances

Copper
Proto-Oncogene Proteins c-akt
Glycogen Synthase Kinase 3