The Role of VDR in Phosphorylation in Vitamin D-Induced Apoptosis
Abstract
Vitamin D3 compounds offer an alternative approach to anti-hormonal therapies for human breast cancer. l,25-Dihydroxyvitrnain D3 (1 ,25-D3) acts through the nuclear vitamin D receptor (VDR), a phosphoprotein, which can be phosphorylated by protein kinase C (PKC) and casein kinase II to modulate gene expression. Our lab has shown that 1 ,2S-D3 induces apoptosis in MCF-7 cells by disruption of initochondrial function which is associated with Bax translocation to mitochondria, cytocinome C release, and production of reactive oxygen species (ROS). Fluorescence microscopy showed direct evidence of Bax translocation to the initochondria after treatment with 1 ,25-D3 in MCF-7 cells. TPA (a PKC activator) did not induce cytocinome C release or Bax translocation, thus demonstrating that it has no effect on mitochondria. However, when the MCF-7D3Res cells (a vitamin D3-resistant variant) were treated with 1 ,25-D3 in the presence of TPA, the cells displayed apoptotic morphology and redistribution of both cytochrome C and Bax. The observation that the phorbol ester TPA can sensitize the vitamin D3-resistant variant to the effects of 1 ,25-D3 suggests an important role for phosphorylation in dictating sensitivity to vitamin D3 mediated apoptosis. This study indicates that the effects of 1 ,25-D3 on mitochondrial disruption might be sensitized through activators of PKC.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2001
- Accession Number
- ADB274478
Entities
People
- Carmen Narvaez
- JoEllen Welsh
Organizations
- University of Notre Dame