Arsenite-induced endoplasmic reticulum-dependent apoptosis through disturbance of calcium homeostasis in HBE cell line.

Calcium (Ca2+ ) is a ubiquitous cell signal responsible for multiple fundamental cellular functions, including apoptosis. Whether the homeostasis of Ca2+ is involved in arsenite-induced apoptosis remains unclear. In this study, we observed that arsenite significantly elevated the intracellular Ca2+ concentration in a dose- and time-dependent manner. By using the Ca2+ -ATPase inhibitor, thapsigargin, and the inositol 1,4,5- trisphosphate receptors (IP3Rs) inhibitor, heparin, we further confirmed that the disturbance of endoplasmic reticulum (ER) Ca2+ homeostasis caused Ca2+ overload in the cells. Moreover, loss of ER Ca2+ homeostasis also led to ER stress, mitochondrial dysfunction, and NF-κB activation. Importantly, pretreatment of cells with heparin remarkably attenuated the elevated cell apoptosis induced by arsenite, but inhibition of ER Ca2+ uptake with thapsigargin exacerbated arsenite-induced cell damage significantly. Together, we demonstrated for the first time that arsenite disturbed the Ca2+ homeostasis in ER, which subsequently led to ER stress, mitochondrial dysfunction, and NF-κB nuclear translocation, and thus consequently triggering cell apoptosis. Our findings indicate regulation of disrupted Ca2+ homeostasis in ER may be a potential strategy for prevention of arsenite toxicity.