Metformin combined with glucose starvation synergistically suppress triple-negative breast cancer by enhanced unfolded protein response

Metformin (MET) is a well-documented drug used in the treatment of type II diabetes. Recent studies have revealed its potential anti-tumor effects in various types of cancer. However, the dosage of MET required to exhibit anti-tumor activity is considerably higher than the clinically recommended dosage. In this study, we investigated the synergistical anti-tumor effect of glucose deprivation and MET in MDA-MB-231 cells, which represents a triple-negative breast cancer subtype (TNBC). Our findings demonstrate that glucose deprivation significantly enhances the anti-tumor activity of MET by reducing cell proliferation and increasing cell apoptosis. RNA-seq was performed to identify the key molecules involved in this process. Our results indicate that unfolded protein response of endoplasmic reticulum (UPRER) was significantly activated upon glucose starvation combining with MET compared to glucose starvation alone. Notably, the combined treatment significantly activated UPRER signaling pathway through ATF4/ATF3/CHOP axis, due to enhanced UPRER stress. In conclusion, our study suggests that the synergistic effects of MET and glucose deprivation suppress cell proliferation in TNBC by activating pro-apoptotic molecules through UPRER stress. These findings have potential implications for the anti-tumor application of MET in TNBC.