The role of STIM1 in the Cr(VI)-induced [Ca2+]i increase and cell injury in L-02 hepatocytes

Hexavalent chromium [Cr(VI)] is a potent cytotoxin and carcinogen. In recent years, drinking water contamination with Cr(VI) has become a worldwide problem of significant public health importance, thus much attention has been paid to the investigation of Cr(VI)-induced hepatotoxicity. The concentration of intracellular calcium ions ([Ca2+](i)) was found to be increased after Cr(VI) exposure, but the exact underlying mechanisms involved in the Ca2+ homeostasis imbalance remain poorly characterized. In the present study, by utilizing the antagonist of store-operated calcium channels (SOCCs) 2-aminoethoxydiphenyl borate (2-APB), small interfering RNA against stromal interaction molecule 1 (si-STIM1) and antioxidant N-acetylcysteine (NAC), we found that Cr(VI) induces [Ca2+](i) increase, cell viability loss and transaminase (AST/ALT) leakage, and that these could be suppressed by both 2-APB and si-STIM1. NAC significantly alleviated Cr(VI)-induced up-regulation of STIM1, phosphorylated-extracellular-signal-regulated kinases 1 and 2 (p-ERK1/2), ERK1/2 and nuclear factor kB (NF-kappa B). By utilizing the ERK inhibitor U0126 and the NF-kB inhibitor pyrrolidine dithiocarbamate (PDTC), we confirmed that STIM1 can be regulated by ERK and NF-kB. Thus we concluded that STIM1 plays a role in the Cr(VI)-induced [Ca2+] i increase and cell injury. Our current data provide new insights into the mechanisms of STIM1 function in Cr(VI)-induced hepatotoxicity, and may provide experimental clues for the prevention and treatment of liver diseases in the occupational population exposed to Cr(VI).