Antiapoptotic oncoprotein Bcl-2 has extramitochondrial actions due to its localization on the endoplasmic reticulum (ER); however, the specific mechanisms of such actions remain unclear. Here we show that Bcl-2 overexpression in LNCaP prostate cancer epithelial cells results in downregulation of store-operated Ca²⁺ current by decreasing the number of functional channels and inhibiting ER Ca²⁺ uptake through a reduction in the expression of calreticulin and SERCA2b, two key proteins controlling ER Ca²⁺ content. Furthermore, we demonstrate that Ca²⁺ store depletion by itself is not sufficient to induce apoptosis in Bcl-2 overexpressing cells, and that sustained Ca²⁺ entry via activated store-operated channels (SOCs) is required as well. Our data therefore suggest the pivotal role of SOCs in apoptosis and cancer progression.