Vitamin D/calcium‐mediated apoptosis in cancer cells and adipocytes

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1,25(OH)2D3 (1,25D) regulates variety of signaling pathways via intracellular Ca2+. Modulating apoptosis is emerging as a strategy for treatment and prevention of cancer and obesity. Cellular Ca2+ has been implicated in triggering apoptosis, however vitamin D/Ca2+‐dependent targets involved in apoptotic signaling have not been identified. We investigated mechanisms of 1,25D‐induced Ca2+ signaling and Ca2+‐mediated apoptosis in cancer cells and adipocytes. The results obtained demonstrate that 1,25D regulates Ca2+ entry from the extracellular space, Ca2+ mobilization from intracellular stores and intracellular Ca2+buffering. We have also shown that that the apoptotic Ca2+ signal represents a sustained increase in [Ca2+]i reaching elevated, but not cytotoxic levels. The apoptotic Ca2+ signal induced by 1,25D in breast cancer cells and mature adipocytes is associated with activation of Ca2+‐dependent μ‐calpain and Ca2+/calpain‐dependent caspase‐12. Activation of these proteases appears to be sufficient for execution of apoptosis. Normal mammary epithelial cells are resistant to induction of apoptosis with 1,25D due to their large Ca2+ buffering capacity. These results indicate that 1,25D‐induced cellular Ca2+ signal can act as an apoptotic initiator that directly recruits Ca2+‐dependent apoptotic effectors capable of executing apoptosis. Supported by USDA 2009‐35200‐05008 and SD00H325.