Inhibiting ROS-TFE3-dependent autophagy enhances the therapeutic response to metformin in breast cancer

Abstract

Autophagy modulation is a potential therapeutic strategy for breast cancer, and a previous study indicated that metformin exhibits significant anti-carcinogenic activity. However, the ability of metformin to induce autophagy and its role in breast cancer cell death remains unclear. In this study, we exposed MCF-7 cells to different concentrations of metformin (2.5, 5, and 10 mM) for 48 h, and metformin-induced significant apoptosis in the MCF-7 cells. The expression levels of CL-PARP (poly(ADP-ribose) polymerase 1) and the ratio of BAX to BCL-2 were significantly increased. In addition to apoptosis, we showed that metformin increased autophagic flux in MCF-7 cells, as evidenced by the upregulation of LC3-II and downregulation of P62/SQSTM1. Moreover, pharmacological or genetic blocking of autophagy increased metformin-induced apoptosis, indicating a cytoprotective role of autophagy in metformin-treated MCF-7 cells. Mechanistically, metformin-induced TFE3 dephosphorylation activated TFE3 nuclear translocation and increased of TFE3 reporter activity, which contributed to lysosomal biogenesis and the expression of autophagy-related genes and, subsequently, initiated autophagy in MCF-7 cells. Importantly, we found that metformin triggered the generation of reactive oxygen species (ROS) in MCF-7 cells. Furthermore, N-acetyl-l-cysteine (NAC), a ROS scavenger, abrogated the effects of metformin on TFE3-dependent autophagy. Notably, TFE3 expression positively correlated with breast cancer development and poor prognosis in patients. Taken together, these data demonstrate that blocking ROS-TFE3-dependent autophagy to enhance the activity of metformin warrants further attention as a treatment strategy for breast cancer.

Luzindole attenuates LPS/d-galactosamine-induced acute hepatitis in mice

“…For example, treatment with melatonin induced apoptosis in gastric cancer cells, breast cancer cells, cervical cancer cells and osteoblastic cells. [29][30][31][32] Treatment with melatonin also enhanced apoptosis induced by other stimulators such as docetaxel and cisplatin. 31,33 Interestingly, it has been reported that treatment with melatonin induced apoptosis in hepatoma cells.…”

Metformin triggers the intrinsic apoptotic response in human AGS gastric adenocarcinoma cells by activating AMPK and suppressing mTOR/AKT signaling

“…The epidemiological studies have suggested that the use of metformin is associated with a decreased incidence of cancer, and improved prognosis and cancer-associated mortality in patients with T2D (13,14). The anticancer effects of metformin have been reported in breast (15,16), colorectal (17), liver (18), cervical (19), endometrial (20), gastric (21), lung (22), ovarian (23), prostate (24), pancreatic (25) and renal (26) cancer. Various studies have demonstrated that the anticancer mechanisms of metformin are mediated via the AMPK/mammalian target of rapamycin (mTOR) cascade, and the signaling is dependent on AMPK activation leading to inhibition of mTOR that represses protein synthesis, cell proliferation, cell cycle progression and apoptotic cell death (27-29).…”

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“…Summing up, the effect of autophagy during treatment with various chemotherapeutic drugs is not predictable and depends on many factors, including the type of cancer. For example, exposure to metformin promoted the myeloma cell death by activating autophagy but led to the survival of breast cancer cells by stimulating protective autophagy [153,154]. Several studies have shown contradictory results upon autophagy inhibition in conjunction with the effect of sorafenib on human hepatocellular carcinoma cells [155,156].…”