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Differential regulation of survivin expression and apoptosis by vitamin D3 compounds in two isogenic MCF-7 breast cancer cell sublines.
- Source :
-
Oncogene [Oncogene] 2005 Feb 17; Vol. 24 (8), pp. 1385-95. - Publication Year :
- 2005
-
Abstract
- Although both the antiapoptotic function of survivin and vitamin D3 (VD3)-mediated cell growth inhibition and apoptosis have been extensively studied, it is not known whether survivin plays a role in VD3 compound-mediated cell growth inhibition and apoptosis induction. Using an isogenic model of MCF-7 breast adenocarcinoma cells (MCF-7E and MCF-7L sublines that are sensitive and resistant to VD3 compounds), we found that VD3 compounds effectively downregulated survivin in VD3-sensitive MCF-7E cells, which was associated with VD3-induced apoptosis. In contrast, VD3 compounds failed to downregulate survivin in VD3-resistant MCF-7L cells, which showed resistant to VD3-induced apoptosis. However, inhibition of survivin expression by small interfering RNA (siRNA) induced cell death per se and further sensitized VD3-induced apoptosis in MCF-7L cells, indicating that the inability of these cells to respond to VD3 is due to the failure to downregulate survivin. Forced expression of survivin not only blocked VD3-mediated G1 cell accumulation but also increased S and G2/M cell populations. VD3 treatment rapidly triggered the activation of p38 MAPK signaling in MCF-7E cells but not in MCF-7L cells. Moreover, inhibition of p38 activation diminished VD3-mediated survivin inhibition and partially rescued VD3-induced cell death. We further showed that VD3 increased the expression of TGF(beta)1 and TGF(beta) receptor 2, and that blocking the function of TGF(beta) receptor 2 diminished VD3 compound-mediated survivin downregulation. Thus, we propose that the VD3 compound-induced growth inhibition and apoptosis induction are at least partially dependent on survivin downregulation via VD3-induced TGFbeta signaling and the activation of p38 MAPK pathway. Targeting survivin through these pathways may lead to novel applications for cancer therapeutics.
- Subjects :
- Cell Line, Tumor
Cholecalciferol analogs & derivatives
Cholecalciferol physiology
Down-Regulation physiology
Female
Humans
Inhibitor of Apoptosis Proteins
Microtubule-Associated Proteins metabolism
Neoplasm Proteins
Phosphorylation
RNA, Small Interfering genetics
Survivin
Transforming Growth Factor beta physiology
p38 Mitogen-Activated Protein Kinases antagonists & inhibitors
p38 Mitogen-Activated Protein Kinases metabolism
Adenocarcinoma genetics
Apoptosis genetics
Breast Neoplasms genetics
Cholecalciferol pharmacology
Gene Expression Regulation, Neoplastic physiology
Microtubule-Associated Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 0950-9232
- Volume :
- 24
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 15608672
- Full Text :
- https://doi.org/10.1038/sj.onc.1208330