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

Fengzhi Li, Xiang Ling, Huayi Huang, Lisa Brattain, Pasha Apontes, Jianguo Wu, Lise Binderup, Michael G. Brattain

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

Although both the antiapoptotic function of survivin and vitamin D 3 (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 TGFβ1 and TGFβ receptor 2, and that blocking the function of TGFβ 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 TGFβ signaling and the activation of p38 MAPK pathway. Targeting survivin through these pathways may lead to novel applications for cancer therapeutics.

Original languageEnglish (US)
Pages (from-to)1385-1395
Number of pages11
JournalOncogene
Volume24
Issue number8
DOIs
StatePublished - Feb 17 2005
Externally publishedYes

Keywords

  • Apoptosis
  • MCF-7 breast cancer cell
  • Survivin
  • Vitamin D
  • p38 MAPK

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Li, F., Ling, X., Huang, H., Brattain, L., Apontes, P., Wu, J., Binderup, L., & Brattain, M. G. (2005). Differential regulation of survivin expression and apoptosis by vitamin D3 compounds in two isogenic MCF-7 breast cancer cell sublines. Oncogene, 24(8), 1385-1395. https://doi.org/10.1038/sj.onc.1208330