Abstract
Resistance to therapy is a major obstacle for the effective treatment of cancer. Expression of synuclein-gamma (SNCG) has been associated with poor prognosis and resistance to therapy. While reports on SNCG overexpression contributing to chemoresistance exist, limited information is available on the relationship between SNCG and radioresistance of cancer cells. Here we investigated the role of SNCG in radiation resistance in breast cancer cells. siRNA mediated knockdown of SNCG (siSNCG) markedly reduced SNCG protein level compared to scrambled siRNA (siScr) treatment. Furthermore, siSNCG treatment sensitized Estrogen Receptor-positive breast cancer cells (MCF7 and T47D) to ionizing radiation at 4 to 12 Gy as evidenced by the significant increase of apoptotic or senescent cells and reduction in clonogenic cell survival in siSNCG treated cells compared to siScr treated cells. On the other hand, we established an in vitro model of SNCG ectopic expression by using a triple-negative breast cancer cell line (SUM159PT) to further investigate the radioprotective effect of SNCG. We showed that ectopic expression of SNCG significantly decreased apoptosis of SUM159PT cells and enhanced clonogenic cell survival after radiation treatment. At the molecular level, after irradiation, the p53 pathway was less activated when SNCG was present. Conversely, p21Waf1/Cip1 expression was upregulated in SNCG-expressing cells. When p21 was down-regulated by siRNA, radiosensitivity of SNCG-expressing SUM159PT cells was dramatically increased. This suggested a possible connection between p21 and SNCG in radioresistance in these cells. In conclusion, our data provide for the first time experimental evidence for the role of SNCG in the radioresistance of breast cancer cells.
Highlights
Breast cancer is the most frequently diagnosed cancer and one of the leading causes of cancer death in women worldwide
SNCG protein was not detected in triple negative breast cancer cell lines, such as MDA-MB-468, MDA-MB-231, and SUM159PT cells, neither in hTERT-HME1 cells (Figure 1B)
It has been reported that SNCG expression was upregulated in irradiated human breast cancer cells and this tumor cell-secreted SNCG
Summary
Breast cancer is the most frequently diagnosed cancer and one of the leading causes of cancer death in women worldwide. In 2012, the number of newly diagnosed cases in the world was estimated at 1.7 million, which represents 25% of all cancer cases in women [1]. Dramatic advances have been made in the effectiveness of anti-cancer therapies, the death rate remains relatively high for breast cancer patients due to hard-to-treat metastatic and recurrent tumors. Radiation therapy is a useful cancer treatment strategy and is a highly cost-effective single-modality treatment. For in situ and infiltrating breast cancer, radiotherapy significantly reduces the risk of local recurrence and increases overall survival [2]. It is necessary to develop new biomarkers that predict the effectiveness of radiotherapy
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