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

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 TGFb1 and TGFb receptor 2, and that blocking the function of TGFb 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 TGFb signaling and the activation of p38 MAPK pathway. Targeting survivin through these pathways may lead to novel applications for cancer therapeutics.

Selenium inhibition of survivin expression by preventing Sp1 binding to its promoter

“…However, it has been shown that expression of survivin is critical for CD34+ hemotopoitic cells to go into cell cycle from G 0 -G 1 to S and G 2 -M phases (46,47). Moreover, down-regulation of survivin by vitamin D compounds has been shown to be essential for vitamin D3 -induced G 1 -G 0 cell arrest (42). Additionally, it has been also shown that up-regulation of survivin by Taxol is independent from Taxol-mediated Research.…”

“…A scramble sequence (5 ¶-CAGUCGCGUUUG-CGACUGGTT) and reverse chain (5 ¶-CCAGUCGCAAAC-GCGACUGTT) was not present in mammalian cells by BLAST search at National Center for Biotechnology Information. The effectiveness of the survivin small interfering RNA on survivin inhibition was 75% to 90% and confirmed in HeLa cells and MCF-7 cells (42). One day before transfection, 3 Â 10 5 cells were seeded in six-well plate.…”

Survivin, a cancer target with an emerging role in normal adult tissues

“…This may be due to inactivation of retinoblastoma or p53 in HeLa cells (98) or selective expression of survivin during mitosis in cancer cells. However, survivin expression in Ki-67-negative breast cancer cells (3), retinoblastoma phosphorylation by survivin resulting from its interaction with Cdk4/p16 INK4a and activation of Cdk2/cyclin E complex in hepatoma cells (12), and resistance to vitamin D -mediated G 1 arrest associated with increased S + G 2 -M phase by ectopic survivin in MCF7 breast cancer cells (14) suggest that survivin may also regulate G 1 -S transition in some cancer cells.…”

“…Survivin disruption in HeLa cells induces aberrant mitosis and polyploidy (5) and homozygous survivin deletion in mice results in early embryonic death from disrupted microtubule formation and polyploidy (6), showing a role for survivin in cell division. Although survivin expression is associated with cell cycle progression and regulation of mitosis in most transformed cell systems investigated (1 -3, 7), it also regulates G 1 -S transition in T lymphocytes (8,9), normal hematopoietic progenitor cells (10,11), hepatoma cells (12,13), and breast cancer cells (14).…”

Antineoplastic effects of 1,25(OH)2D3 and its analogs in breast, prostate and colorectal cancer

“…Inhibition of epidermal growth factor receptor (EGFR) expression by 1,25(OH) 2 D 3 is also thought to aid cell growth inhibition (McGaffin & Chrysogelos 2005, Belochitski et al 2007 as well as the downregulation of survivin, an inhibitor of apoptosis (Li et al 2005, Koike et al 2011) and platelet-derived growth factor downregulation by 1,25(OH) 2 D 3 . A study with CRC cells suggests that 1,25(OH) 2 D 3 -mediated antiproliferative effects are dependent on the dual role of the VDR: first, as a transcriptional factor and secondly, as a nongenomic activator of the Rho-ROCK-p38MAPK-MSK signaling pathway (Ordonez-Moran et al 2008).…”