The relationship between anticancer effect of metformin and the transcriptional regulation of certain genes (CHOP, CAV-1, HO-1, SGK-1 and Par-4) on MCF-7 cell line

Abstract

BACKGROUND: 1,1-dimethylbiguanide hydrochloride (biguanide metformin) is a hypoglycemic agent that is widely used in the treatment of Type 2 diabetes. Use of metformin was found to be associated with the lower risk of cancer. It is suggested that metformin has an anticancer and antiproliferative effect and affects the apoptosis by activating the AMPK and inhibiting the mammalian target of rapamycin (mTOR). Although the effects of metformin treatment of various types of cancers are defined with many mechanisms, the literature provides only sufficient information about how it affects the SGK-1, Par-4 and Cav-1 mRNA expressions and the impact of this effect on cytotoxicity. The breast cancer is globally one of the most important causes of cancer-related mortality for women. We, therefore investigated the possible effects of metmorfin on proliferation, cytotoxicity and some unfolded protein response (UPR) genes in the breast cancer cells (MCF-7). MATERIALS AND METHODS: We administrated 0.31 mM, 2.5 mM and 10 mM of metformin alone and in combination with 2-DG to the MCF-7 cells and monitored the cell viability and proliferation with real-time cell analyzer system for 48 hours. We also measured CHOP, Cav-1, HO-1, SGK-1 and Par-4 genes mRNA expression levels using Real Time-Polymerase Chain Reaction (RTPCR). We considered the GAPDH gene as reference gene and the control groups as calibrator. We performed an analysis for relative gene expressions of the study groups. RESULTS: Metformin caused transcriptional regulation of UPR and tumor-related genes in MCF-7 cells and inhibited the proliferation depending on the dose, resulting in cytotoxic effect. CONCLUSIONS: We consider that administration of metformin with chemotherapeutic agents could be an effective method in treatment of breast cancer through mechanisms such as reduced resistance to chemotherapy and increased cytotoxic activity.