Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 276, Issue 12, Pages 9101-9107Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M006876200
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- NCI NIH HHS [CA69700] Funding Source: Medline
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Vitamin D-3 compounds are currently in clinical trials for human breast cancer and offer an alternative approach to anti-hormonal therapies for this disease. 1 alpha ,25-Dihydroxyvitamin D-3 (1 alpha ,25(OH)(2)D-3), the active form of vitamin D-3, induces apoptosis in breast cancer cells and tumors, but the underlying mechanisms are poorly characterized. In these studies, we focused on the role of caspase activation and mitochondrial disruption in 1 alpha ,25(OH)(2)D-3-mediated apoptosis in breast cancer cells (MCF-7) in vitro. The effect of 1 alpha ,25(OH)(2)D-3 on MCF-7 cells was compared with that of tumor necrosis factor alpha, which induces apoptosis via a caspase-dependent pathway. Our major findings are that 1 alpha ,25(OH)(2)D-3 induces apoptosis in MCF-7 cells by disruption of mitochondrial function, which is associated with Bax translocation to mitochondria, cytochrome c release, and production of reactive oxygen species. Moreover, we show that Bax translocation and mitochondrial disruption do not occur after 1 alpha ,25(OH)(2)D-3 treatment of a MCF-7 cell clone selected for resistance to 1 alpha ,25(OH)(2)D-3-mediated apoptosis. These mitochondrial effects of 1 alpha ,25(OH)(2)D-3 do not require caspase activation, since they are not blocked by the cell-permeable caspase inhibitor z-Val-Ala-Asp-fluoromethylketone. Although caspase inhibition blocks 1 alpha ,25(OH)(2)D-3-mediated events downstream of mitochondria such as poly(ADP-ribose) polymerase cleavage, external display of phosphatidylserine, and DNA fragmentation, MCF-7 cells still execute apoptosis in the presence of z-Val-Ala-Asp-fluoromethylketone, indicating that the commitment to 1 alpha ,25(OH)(2)D-3-mediated cell death is caspase-independent.
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