STIM1 N-linked glycosylation promotes arsenic-induced malignant phenotype by activating SOCE in bladder epithelial cells.

Epidemiologic research has demonstrated a clear correlation between prolonged exposure to inorganic arsenic and an elevated risk of bladder cancer, but the specific mechanisms are unknown. Calcium ions (Ca2+), as key second messengers, are crucial in cellular physiological and pathological processes. Loss of Ca2+ homeostasis is thought to be an important driver of malignant disease. In this study, C57BL/6 mice were treated with 0, 8, 20 and 50 mg/L NaAsO2 via drinking water during 20 weeks, and human normal bladder epithelial cells (SV-HUC-1) received continuous exposure to 0.5 μM NaAsO2 over 40 weeks. The results revealed that long-term arsenic treatment led to elevated Ca2+ levels in SV-HUC-1 cells and enhanced cell proliferation, stemness, and epithelial-mesenchymal transition (EMT). Our study revealed that store-operated calcium entry (SOCE) was essential in arsenic-induced elevation of Ca2+ levels. STIM1 serves as a critical mediator of arsenic-triggered malignant transformation in urothelial cells by regulating store-operated calcium channels (SOCC). STIM1 undergoes N-linked glycosylation at its N131 site. This post-translational modification is essential for proper STIM1 localization and binding with ORAI1. The evidence, similar to the cellular experiments in vitro, was also observed in animal experiments in vivo. Our research results provide a new mechanism for the role of calcium homeostasis imbalance in arsenic-induced initiation and progression of bladder cancer.