miR-۲۱-۵p / SESN۱, axis involved in radiosensitivity of Breast cancer cells treated with metformin

Breast cancer is the most prevalent form of cancer and is one of the leading causes of death among women globally. Radiation therapy, commonly using X-rays, is recognized as an effective procedure for treating breast cancer. However, some cancer cells become resistant to radiation therapy, posing a significant challenge in radiotherapy and serving as the leading cause of treatment failure. Metformin, a drug traditionally used to manage type ۲ diabetes, has been shown to enhance the radio sensitivity of cancer cells, including those in breast cancer. Despite this, the exact molecular mechanisms of its radio sensitivity effects are not fully understood. In this study, we investigated one of these mechanisms in detail. First, radiation-resistant breast cancer cells were constructed. Then, the expression rate of miR-۲۱-۵p and SESN۱ gene in resistant and control cells was checked by Quantitative Real-time PCR (qRTPCR). After treating the cell lines with different concentrations of metformin at various intervals, the rate of cell proliferation and cell death was checked by CCK-۸ assay and flow cytometry. The Western blot method was also used to confirm the expression of some genes. Our results showed that the expression of miR-۲۱-۵p was upregulated in radiation-resistant cancer cells (۱.۸±۰.۶۵) (P<۰.۰۰۰۱) MCF-۷ cell line and (۱.۶±۰.۴۲) (P<۰.۰۰۱) MBA-MD-۲۳۱ cell line, while the expression of SESN۱ was downregulated (۰.۴۶±۰.۱۲) (P<۰.۰۰۰۱) MCF-۷ cell line and (۰.۴۲±۰.۲۲) (P<۰.۰۰۱) MBA-MD-۲۳۱ cell line. Metformin increased the radio sensitivity of breast cancer cells in a dose and time-dependent manner. Additionally, metformin treatment decreased the expression of miR-۲۱-۵p (۰.۴۷±۰.۳۲) (P<۰.۰۰۰۱) MCF-۷ Cell line and (۰.۴۵±۰.۲۱) (P<۰.۰۰۱) MBA-MD-۲۳۱ cell line and increased the expression of SESN۱(۱.۶۵±۰.۷۲) (P<۰.۰۰۰۱) MCF-۷ cell line and (۱.۷۳±۰.۵۲) (P<۰.۰۰۰۱) MBA-MD-۲۳۱ cell line. The function of metformin was reversed by miR-۲۱-۵p inhibitors or the transfection of SESN۱ overexpressing plasmids. In conclusion, based on this research results, metformin enhances the radio sensitivity of breast cancer cells via modulating the expression of miR-۲۱-۵p and SESN۱, indicating its potential to increase the effectiveness of radiotherapy in breast cancer treatment.

کلیدواژه ها:

Breast cancer ، Metformin ، Radiation therapy ، miR-۲۱-۵p ، SESN۱