1. Academic Validation
  2. Elevated aerobic glycolysis driven by p62-mTOR axis promotes arsenic-induced oncogenic phenotypes in human mammary epithelial cells

Elevated aerobic glycolysis driven by p62-mTOR axis promotes arsenic-induced oncogenic phenotypes in human mammary epithelial cells

  • Arch Toxicol. 2024 Mar 14. doi: 10.1007/s00204-024-03709-2.
Yongfang Li 1 2 3 Jiao Liu 2 Dianqi Yao 1 2 3 Zijun Guo 1 2 3 Xuheng Jiang 2 Chengwen Zhang 1 2 3 Litong Qu 1 2 3 Yuyan Liu 4 Yuxin Hu 1 2 3 Lanyue Gao 1 2 3 Yi Wang 1 2 3 Yuanyuan Xu 5 6 7
Affiliations

Affiliations

  • 1 Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education, Shenyang, People's Republic of China.
  • 2 School of Public Health, China Medical University, Shenyang, People's Republic of China.
  • 3 Key Laboratory of Toxic and Biological Effects of Arsenic (China Medical University), Liaoning Province, Shenyang, People's Republic of China.
  • 4 Department of Clinical Epidemiology, the Fourth Affiliated Hospital, China Medical University, Shenyang, People's Republic of China.
  • 5 Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education, Shenyang, People's Republic of China. yyxu@cmu.edu.cn.
  • 6 School of Public Health, China Medical University, Shenyang, People's Republic of China. yyxu@cmu.edu.cn.
  • 7 Key Laboratory of Toxic and Biological Effects of Arsenic (China Medical University), Liaoning Province, Shenyang, People's Republic of China. yyxu@cmu.edu.cn.
Abstract

Chronic arsenic exposure is considered to increase the risk of breast Cancer. p62 is a multifunctional adaptor protein that controls myriad cellular processes and is overexpressed in breast Cancer tissues. Although previous studies have indicated the involvement of p62 accumulation in arsenic tumorigenesis, the underlying mechanism remains obscure. Here, we found that 0.1 µM or 0.5 µM arsenite exposure for 24 weeks induced oncogenic phenotypes in human mammary epithelial cells. Elevated aerobic glycolysis, cell proliferation capacity, and activation of p62-mTOR pathway, as indicated by increased protein levels of p62, phosphorylated-mTOR (p-mTOR) and hypoxia-inducible factor 1α (HIF1α), were observed in chronically arsenite-exposed cells, and of note in advance of the onset of oncogenic phenotypes. Moreover, p62 silencing inhibited acquisition of oncogenic phenotypes in arsenite-exposed cells. The protein levels of p-mTOR and HIF1α, as well as aerobic glycolysis and cell proliferation, were suppressed by p62 knockdown. In addition, re-activation of p‑mTOR reversed the inhibitory effects of p62 knockdown. Collectively, our data suggest that p62 exerts an oncogenic role via mTORC1 activation and acts as a key player in glucose metabolism during arsenite-induced malignant transformation, which provides a new mechanistic clue for the arsenite carcinogenesis.

Keywords

Aerobic glycolysis; Arsenite; Breast cancer; mTORC1; p62.

Figures
Products