Survivin plays as a resistant factor against tamoxifen-induced apoptosis in human breast cancer cells

Abstract

Tamoxifen has been the mainstay of endocrine therapy for estrogen receptor-positive breast cancer. However, approximately 40% of breast cancer patients do not respond to tamoxifen treatment. Further, most tumors eventually acquire tamoxifen resistance. Therefore, it is necessary to develop effective modalities to enhance the efficacy of tamoxifen in breast cancer treatment. In this study, we investigated the mechanism by which breast cancer cells develop resistance against tamoxifen from the viewpoint of tamoxifen-induced apoptosis. Overexpression of the anti-apoptotic molecule survivin rendered the human breast cancer cells MCF-7 resistant to tamoxifen-induced apoptosis. To examine whether the down-regulation of survivin can enhance tamoxifen-induced apoptosis, we introduced siRNA targeting the survivin gene (survivin-siRNA) into MCF-7 cells. Survivin-siRNA transfection not only induced apoptosis without tamoxifen treatment but also augmented the tamoxifen-induced apoptosis. We have previously demonstrated that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HRIs), which are widely used to reduce the serum cholesterol levels in hypercholesterolemia patients, decreases survivin expression in colon cancer cells. To develop a pharmacological approach for improving the efficacy of tamoxifen treatment, we determined whether HRIs can enhance tamoxifen-induced apoptosis. Lovastatin, an HRI, down-regulated the expression of survivin protein in MCF-7 cells in a dose-dependent manner. In addition, the proportion of apoptotic cells induced by the tamoxifen and lovastatin combination was greater than the theoretical additive effect. These results suggest that survivin may function as a factor inducing resistance against tamoxifen-induced apoptosis, and the combined use of tamoxifen and HRI may be a novel approach to overcome tamoxifen resistance in breast cancer.

Sensitization of human melanoma cells by tamoxifen to apoptosis induction by pancratistatin, a nongenotoxic natural compound

“…Earlier studies have shown that TAM may also act on the mitochondria to induce apoptosis [12,21]. Recent studies have used a low concentration of TAM (5 mmol/l) in combination with another drug (lovastatin) in MCF-7 [22,23]. Hoechst staining on A375 cells treated with TAM at both its effective concentration (10 mmol/l) and half-effective concentration (5 mmol/l) resulted in a very small increase in apoptosis compared with control (Fig.…”

FOXM1 targets XIAP and Survivin to modulate breast cancer survival and chemoresistance

“…Overexpression of inhibitor of apoptosis proteins (IAPs) has been shown as a hallmark of many types of cancer, including breast cancer . IAPs, particularly Survivin and XIAP, are frequently associated to a poor prognosis (Span et al, 2004;Hinnis et al, 2007;Jaffer et al, 2007;Zhang et al, 2011) and drug resistance in neoplastic mammary cells (Moriai et al, 2009;Dean et al, 2009;Flygare et al, 2012;Wang et al, 2010;Zhu et al, 2010). Thus, they have been extensively studied as potential therapeutic targets.…”

Bevacizumab enhances chemosensitivity of hepatocellular carcinoma to adriamycin related to inhibition of survivin expression

“…Growing evidence has indicated that survivin expression plays an essential role in drug resistance and that genetic or pharmacological modulation of survivin expression affects drug effectiveness in apoptosis induction (Li and Ling 2006;Moriai et al 2008). In endothelial cells (ECs), VEGF can up-regulate survivin expression through the PI3 K/Akt signaling pathway to escape from apoptosis (O'Connor et al 2000), which can be suppressed by survivin targeting treatment (Mesri et al 2001).…”