1. Academic Validation
  2. Low-dose arsenite causes overexpression of EGF, TGFα, and HSP90 through Trx1-TXNIP-NLRP3 axis mediated signaling pathways in the human bladder epithelial cells

Low-dose arsenite causes overexpression of EGF, TGFα, and HSP90 through Trx1-TXNIP-NLRP3 axis mediated signaling pathways in the human bladder epithelial cells

  • Ecotoxicol Environ Saf. 2022 Dec 1;247:114263. doi: 10.1016/j.ecoenv.2022.114263.
Peiyu Jin 1 Qing Zhou 2 Shuhua Xi 3
Affiliations

Affiliations

  • 1 Department of Nutrition and Food Hygiene, School of Public Health, China Medical University, No 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning 110122, PR China.
  • 2 Department of Occupational and Environmental Health, School of Public Health, China Medical University, PR China.
  • 3 Department of Occupational and Environmental Health, School of Public Health, China Medical University, PR China. Electronic address: shxi@cmu.edu.cn.
Abstract

Epidemiological studies have demonstrated an increased incidence of bladder Cancer in arseniasis- endemic areas; however, the precise molecular mechanisms remain unknown. Our previous results have shown that the protein levels of EGF, TGFα, and HSP90 in arsenite-treated bladder uroepithelial cells increased markedly and contributed to hyperactivation of EGF receptors. The aim of this study was to further explore the regulatory ways underlying overexpression of EGF, TGFα, and HSP90 in these cells. The present results showed that both Trx and GSH systems were stimulated in arsenite-treated cells, and ROS levels in 2 μM arsenite-treated cells did not changed obviously; however, ROS levels in 4 μM arsenite-treated cells increased significantly. By using the antioxidant and specific inhibitors, we found that in 2 μM arsenite-treated cells, JNK/NF-κB signaling pathway was involved in overexpression of EGF and TGFα, and ERK/NF-κB signaling pathway contributed to HSP90 overexpression, however in 4 μM arsenite-treated cells, both ERK/ and JNK/NF-κB signaling pathways were involved in overexpression of EGF, TGFα, and HSP90, and PI3K/Akt/NF-κB signaling pathway contributed to overexpression of EGF and TGFα. Furthermore, our results also showed that the Trx1-TXNIP-NLRP3 axis was activated in arsenite-treated cells, and played a pivotal role in activation of the signaling pathways involved in overexpression of EGF, TGFα, and HSP90. In conclusion, the Trx1-TXNIP-NLRP3 axis might be activated by arsenite-induced redox imbalance in bladder uroepithelial cells, and mediate the activation of signaling pathways involved in overexpression of EGF, TGFα, and HSP90.

Keywords

Arsenite; Bladder uroepithelial cells; Epidermal growth factor; Human epidermal growth factor receptor; NLRP3 inflammasome; Thioredoxin system.

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