Novel Mediators of Vitamin D Signaling in Cancer and Obesity

The hormone 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) regulates a variety of signaling pathways in health and disease via intracellular Ca2+. An emerging approach in treatment and prevention of cancer and obesity is induction of apoptotic cell death. Cellular Ca2+ signals have been implicated in triggering apoptosis, however vitamin D/Ca2+-dependent mediators involved in apoptotic signaling have not been identified. Our studies reviewed here demonstrate that 1,25(OH)2D3 induces Ca2+-mediated apoptotic death of cancer cells and adipocytes via activation of the novel targets, Ca2+-dependent μ-calpain and Ca2+/calpain-dependent caspase-12. In this pathway -- sustained increase in intracellular Ca2+ → μ-calpain activation → caspase-12 activation → apoptosis -- cellular Ca2+ acts as an apoptotic initiator and directly recruits Ca2+-dependent apoptotic effectors capable of executing apoptosis. Our findings provide a new rationale for evaluating the role of vitamin D in prevention and treatment of cancer and obesity.