Differential regulation of survivin expression and apoptosis by vitamin D3 compounds in two isogenic MCF-7 breast cancer cell sublines

Oncogene. 2005 Feb 17;24(8):1385-95. doi: 10.1038/sj.onc.1208330.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenocarcinoma / genetics*
  • Apoptosis / genetics*
  • Breast Neoplasms / genetics*
  • Cell Line, Tumor
  • Cholecalciferol / analogs & derivatives
  • Cholecalciferol / pharmacology*
  • Cholecalciferol / physiology
  • Down-Regulation / physiology
  • Female
  • Gene Expression Regulation, Neoplastic / physiology*
  • Humans
  • Inhibitor of Apoptosis Proteins
  • Microtubule-Associated Proteins / genetics*
  • 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

Substances

  • BIRC5 protein, human
  • Inhibitor of Apoptosis Proteins
  • Microtubule-Associated Proteins
  • Neoplasm Proteins
  • RNA, Small Interfering
  • Survivin
  • Transforming Growth Factor beta
  • Cholecalciferol
  • p38 Mitogen-Activated Protein Kinases