Arsenic enhances endoplasmic reticulum stress via YTHDC1/AKR1C3 aix to promote the malignant transformation of human urothelial cells

Abstract

Arsenic, a well-established carcinogen, is strongly associated with the development of multiple malignancies, including bladder, skin, and lung cancers. Epidemiological studies have revealed that elevated arsenic concentrations in water sources significantly increase the risk of bladder cancer (BC), which exhibits the highest relative risk among arsenic-induced cancers. Furthermore, patients exposed to arsenic show a greater propensity for developing high-grade malignant tumors. Nevertheless, the precise molecular mechanisms underlying arsenic-induced BC initiation and progression remain incompletely understood. Our experiments revealed a significant upregulation of AKR1C3 expression in human urothelial cells following arsenic exposure. Consistently, rats subjected to long-term arsenic-contaminated drinking water displayed a similar upregulation pattern in bladder epithelial tissues. The overexpression of AKR1C3 showed a pronounced ability to promote arsenic-induced malignant transformation of human urothelial cells, both in vitro and in vivo. Mechanistic studies revealed that arsenic stabilized AKR1C3 mRNA by upregulating YTHDC1, resulting in increased AKR1C3 protein levels. Further investigation into downstream mechanisms indicated that AKR1C3 amplifies endoplasmic reticulum (ER) stress by upregulating ER stress-sensing and transducing proteins-PERK, IRE1, and ATF6-thereby exacerbating the unfolded protein response (UPR). This sustained activation of the UPR enhances cellular adaptation to arsenic-induced stress, perpetuating its oncogenic effects and ultimately driving the malignant transformation of urothelial cells. Our findings delineate the specific role and mechanistic basis of AKR1C3 in arsenic-induced bladder carcinogenesis, providing a theoretical framework for developing preventive and therapeutic strategies against this malignancy.

Keywords: AKR1C3; Bladder cancer; Endoplasmic reticulum stress; YTHDC1.