Ca²⁺/CaN-mediated NF-κB and NFAT activation drives arsenic-induced bladder epithelial pre-malignant behavior

This is the authors' abstract. We don't add key points for this paper.

Arsenic, a widely distributed environmental contaminant, poses a significant global public health challenge, affecting hundreds of millions of individuals worldwide. Chronic arsenic exposure is a well-established risk factor for bladder cancer, however, the fundamental underlying molecular processes mechanisms remain incompletely understood. In this study, C57BL/6 mice were exposed to sodium arsenite (NaAsO₂; 0, 8, 20, and 50 mg/L) through drinking water for 20 weeks, and human normal bladder epithelial cells (SV-HUC-1) were chronically treated with 0.5 μM NaAsO 2 for 40 weeks. The results demonstrate that long-term arsenic exposure induces aberrant growth of bladder epithelial cells both in vitro and in vivo . Mechanistically, arsenic increased intracellular Ca 2 + levels, which were played a role in promoting pre-malignant phenotypes. This study identified calcium-dependent calcineurin (CaN) as a key downstream effector of Ca 2+ signaling, with its activity enhanced by arsenic-induced Ca 2+ elevation. Long-term arsenic exposure promoted pre-malignant cellular behavior through CaN activation. Furthermore, CaN enhanced the activity of nuclear factor kappa B (NF-κB) and nuclear factor of activated T cells (NFAT) pathways, both of which are closely associated with tumorigenesis in arsenic-exposed bladder epithelial cells. Pharmacological inhibition of CaN effectively suppressed arsenic-induced activation of both NF-κB and NFAT pathways. Finally, this study demonstrated that store-operated calcium entry (SOCE) serves as the source of elevated intracellular Ca²⁺ levels, and that arsenic activates NF-κB and NFAT signaling pathways through SOCE-mediated Ca²⁺ influx. These findings reveal a mechanistic link whereby chronic arsenic exposure induces SOCE-mediated Ca 2+ elevation, activates CaN, and subsequently promotes NF-κB and NFAT pathway activation, ultimately driving pre-malignant behavior of bladder epithelial cells.