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  • Title: Induction of apoptosis by 1,25-dihydroxyvitamin D3 in MCF-7 Vitamin D3-resistant variant can be sensitized by TPA.
    Author: Narvaez CJ, Byrne BM, Romu S, Valrance M, Welsh J.
    Journal: J Steroid Biochem Mol Biol; 2003 Feb; 84(2-3):199-209. PubMed ID: 12711004.
    Abstract:
    Vitamin D(3) compounds offer an alternative approach to anti-hormonal therapies for human breast cancer. 1,25-Dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) acts through the nuclear Vitamin D(3) receptor (VDR), a phosphoprotein and ligand-dependent transcription factor. Our lab has shown that 1,25-(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 (ROS). TPA, a protein kinase C (PKC) activator, does not induce cytochrome c release or Bax translocation, thus demonstrating that it has no effect on mitochondria and apoptosis on its own. However, when the MCF-7(D(3)Res) cells (a Vitamin D(3)-resistant variant) are treated with 1,25-(OH)(2)D(3) in the presence of TPA, the cells displayed apoptotic morphology and redistribution of both cytochrome c and Bax. TPA pretreatment greatly enhances 1,25-(OH)(2)D(3) stimulated 24-hydroxylase luciferase activity and VDR protein expression, although transactivation is lower in the MCF-7(D(3)Res) cells compared to the parental cell line. The observation that the phorbol ester TPA sensitizes the Vitamin D(3)-resistant variant to the effects of 1,25-(OH)(2)D(3) suggests an important role for phosphorylation in dictating sensitivity to Vitamin D(3)-mediated apoptosis. This study demonstrates that the effects of 1,25-(OH)(2)D(3) on mitochondrial disruption might be sensitized through activators of PKC.
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