Calcium efflux from the endoplasmic reticulum regulates cisplatin-induced apoptosis in human cervical cancer HeLa cells.

The function of calcium efflux from the endoplasmic reticulum (ER) in cisplatin-induced apoptosis is not fully understood in cancer cells. The present study used western blot analysis, flow cytometry, immunofluorescence and 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assay to investigate calcium signaling in human cervical cancer cells exposed to cisplatin. In the present study, treatment with cisplatin increased free Ca levels in the cytoplasm and mitochondria of human cervical cancer HeLa cells, which further triggers the mitochondria-mediated and ER stress-associated apoptosis pathways. Notably, blocking calcium signaling using the calcium chelating agent bis-(o-aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid acetoxymethyl ester inhibited cisplatin-induced apoptosis via downregulation of the calcium-dependent proteases, the calpains, and innate apoptosis proteins, such as caspsae-3, caspase-4 and C/EBP homologous protein (CHOP). In addition, use of the inositol triphosphate receptor inhibitor, 2-aminoethyl diphenylborinate, to inhibit calcium efflux from the ER resulted in similar effects. This data indicated that calcium efflux from the ER plays a significant role in cisplatin-induced apoptosis in human cervical cancer HeLa cells, which provides further mechanistic insights into the tumor cell-killing effect of cisplatin and potential therapeutic strategies to improve cisplatin chemotherapy.