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  3. Targeting SLC1A5 blocks cell proliferation through inhibition of mTORC1 in arsenite-treated human uroepithelial cells

Targeting SLC1A5 blocks cell proliferation through inhibition of mTORC1 in arsenite-treated human uroepithelial cells

  • Toxicol Lett. 2021 Jul 1;345:1-11. doi: 10.1016/j.toxlet.2021.03.007.
Sihao Li 1,  Qing Zhou 2,  Weijue Liu 3,  Zhushan Fu 4,  Hanqing Zhao 5,  Shuhua Xi 6
Affiliations

Affiliations

  • 1 Department of Environmental and Occupational Health, School of Public Health, China Medical University, China. Electronic address: shli@cmu.edu.cn.
  • 2 Department of Environmental and Occupational Health, School of Public Health, China Medical University, China. Electronic address: qzhou94@cmu.edu.cn.
  • 3 Department of Environmental and Occupational Health, School of Public Health, China Medical University, China. Electronic address: wjliu@cmu.edu.cn.
  • 4 Department of Environmental and Occupational Health, School of Public Health, China Medical University, China. Electronic address: zsfu@cmu.edu.cn.
  • 5 Department of Environmental and Occupational Health, School of Public Health, China Medical University, China. Electronic address: hqzhao@cmu.edu.cn.
  • 6 Department of Environmental and Occupational Health, School of Public Health, China Medical University, China. Electronic address: shxi@cmu.edu.cn.
PMID: 33781819 DOI: 10.1016/j.toxlet.2021.03.007
Abstract

Arsenic is an environmental contaminant, which is widely distributed in soil, air, and water. There is sufficient evidence to indicate that arsenic increases the risk of bladder Cancer in humans. However, its underlying mechanisms remain elusive. Glutamine (Gln) has multiple functions that promote carcinogenesis. Indeed, Gln transporters on Cancer cells surface are often upregulated. Elevated expression levels of Alanine, serine, cysteine-preferring transporter 2 (ASCT2; SLC1A5) have been reported in many types of human tumors. This study characterized the role of SLC1A5 in cell proliferation in arsenite-treated cells. In short-term experiments, SV-40 immortalized human uroepithelial (SV-HUC-1) cells were treated with Sodium arsenite (NaAsO2) (0, 0.5, 1, 2, 4, 8 μM) for 24 h. In long-term experiments, SV-HUC-1 cells were exposed to 0.5 μM NaAsO2 for 40 weeks. In both short-term and long-term experiments, arsenite increased expression of SLC1A5 by 1.89-fold and 2.25-fold, respectively. Arsenite increased Gln consumption of SV-HUC-1 cells, and Gln starvation inhibited cell proliferation in long-term arsenite-treated cells. Importantly, inhibiting SLC1A5 blocked cell proliferation by downregulating mTORC1 in long-term arsenite-treated cells. Moreover, SLC1A5 regulated mTORC1 in an αKG-dependent manner. Our results suggest that SLC1A5 plays an important role in cell proliferation of arsenite-treated SV-HUC-1 cells.

Keywords

Arsenic; Bladder cancer; Glutamine; SLC1A5; mTORC1.

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