Vitamin D and cellular Ca2+ signaling in breast cancer.
The hormone 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) regulates a variety of signaling pathways via intracellular Ca(2+). Modulation of apoptosis is emerging as a promising strategy for treatment and prevention of cancer. Cellular Ca(2+) has been implicated in triggering of apoptosis, however, the vitamin D/Ca(2+)-dependent targets involved in apoptotic signaling have not been identified. Here, we review our studies on mechanisms of 1,25(OH)(2)D(3)-induced Ca(2+) signaling and Ca(2+)-mediated apoptosis in breast cancer cells. The results obtained demonstrate that 1,25(OH)(2)D(3) regulates Ca(2+) entry from the extracellular space, Ca(2+) mobilization from the intracellular stores and intracellular Ca(2+) buffering. In breast cancer cells, 1,25(OH)(2)D(3) induces the apoptotic Ca(2+) signal, a sustained increase in concentration of intracellular Ca(2+) ([Ca(2+)](i)) reaching elevated, but not cytotoxic levels. This increase in [Ca(2+)](i) is associated with activation of Ca(2+)-dependent μ-calpain and Ca(2+)/calpain-dependent caspase-12. Activation of these proteases appears to be sufficient for the execution of apoptosis in cancer cells. Normal mammary epithelial cells resist induction of apoptosis with 1,25(OH)(2)D(3) due to their large Ca(2+)-buffering capacity. The results indicate that the 1,25(OH)(2)D(3)-induced cellular Ca(2+) signal can act as an apoptotic initiator that directly recruits Ca(2+)-dependent apoptotic effectors capable of executing apoptosis. These findings provide a novel rationale for evaluating the role of vitamin D in prevention and treatment of breast cancer.
Department of Health and Nutritional Sciences, South Dakota State University, Brookings, SD 57007, USA. igor.sergeev@sdstate.edu
Igor N
IN
Sergeev
D017209:Apoptosis; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D020013:Calcium Signaling; D005260:Female; D006801:Humans; D014807:Vitamin D / Q000378:metabolism*
D014807:Vitamin D