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Synuclein gamma expression enhances radiation resistance of breast cancer cells.

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, p21^Waf1/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.

SUBMITTER: Tian L

PROVIDER: S-EPMC6007952 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAlthough radiotherapy following mastectomy was demonstrated to reduce the recurring risk and improve the prognosis of patients with breast cancer, it is also notorious for comprehensive side effects, hence only a selected group of patients can benefit. Therefore, the screening of molecular markers capable of predicting the efficacy of radiotherapy is essential.MethodsWe have established a cohort of 454 breast cancer cases and selected 238 patients with indications for postoperative radiotherapy. Synuclein-γ (SNCG) protein levels were assessed by immunohistochemistry, and SNCG status was retrospectively correlated with clinical features and survival in patients treated or not treated with radiotherapy. Gene Set Enrichment Analysis (GSEA) and survival analysis for online datasets were also performed for further validation.ResultsAmong patients that received radiotherapy (82/238), those demonstrating positive SNCG expression had a 55.0 month shorter median overall survival (OS) in comparison to those demonstrating negative SNCG expression (78.4 vs. 133.4 months, log rank χ (2) = 16.13; p < 0.001). Among the patients that received no radiotherapy (156/238), SNCG status was not correlated with OS (log rank χ (2) = 2.40; p = 0.121). A COX proportional hazard analysis confirmed SNCG as an independent predictor of OS, only for patients who have received radiotherapy. Similar results were also obtained for distant metastasis-free survival (DMFS). A GSEA analysis indicated that SNCG was strongly associated with genes related to a radiation stress response. A survival analysis was performed with online databases consisting of breast cancer, lung cancer, and glioblastoma and further confirmed SNCG's significance in predicting the survival of patients that have received radiotherapy.ConclusionA positive SNCG may serve as a potential marker to identify breast cancer patients who are less likely to benefit from radiotherapy and may also be extended to other types of cancer. However, the role of SNCG in radiotherapy response still needs to be further validated in randomized controlled trials prior to being exploited in clinical practice.

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Synuclein gamma expression enhances radiation resistance of breast cancer cells.

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