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

Oncogene volume 24, pages 1385–1395 (2005)Cite this article

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 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.

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Abbreviations

IAP:

inhibitor of apoptosis

BIR:

baculovirus IAP repeat

VD3:

vitamin D3

PARP:

poly (ADP-ribose) polymerase

TGFβ RII:

transforming growth factor receptor II

TGFβ DNR II:

dominant-negative TGFβ receptor 2

siRNA:

small interfering RNA

DOX:

doxycycline

SDS-PAGE:

sodium dodecyl sulfate-polyacrylamide gel electrophoresis

GAPDH:

glyceraldehyde 3-phosphate dehydrogenase

PI:

propidium iodide

s.d.:

standard deviation

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Acknowledgements

This work was sponsored in part by foundation grants from Wendy Will Case Cancer Fund Inc. (Chicago, IL), Elsa U Pardee Foundation (Midland, Michigan) and Concern Foundation (Beverly Hill, CA) to FL, by NIH R01 grants to MGB (CA72001 and CA38173) and to FL (CA109481), and by shared resources of NIH Cancer Center Support Grant (CA16056) to Roswell Park Cancer Institute.

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Authors and Affiliations

  1. Department of Pharmacology and Therapeutics, Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, NY, USA

    Fengzhi Li, Xiang Ling, Huayi Huang, Lisa Brattain, Pasha Apontes, Jianguo Wu & Michael G Brattain

  2. Department of Biochemistry, Leo Pharmaceutical Products, 55, Denmark

    Lise Binderup

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  1. Fengzhi Li
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Correspondence to Fengzhi Li.

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Li, F., Ling, X., Huang, H. et al. Differential regulation of survivin expression and apoptosis by vitamin D3 compounds in two isogenic MCF-7 breast cancer cell sublines. Oncogene 24, 1385–1395 (2005). https://doi.org/10.1038/sj.onc.1208330

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