Metformin inhibits estrogen‐dependent endometrial cancer cell growth by activating the AMPK–FOXO1 signal pathway

Abstract

Metformin is an oral biguanide commonly used for treating type II diabetes and has recently been reported to possess antiproliferative properties that can be exploited for the prevention and treatment of a variety of cancers. The mechanisms underlying this effect have not been fully elucidated. Our study shows a marked loss of AMP‐activated protein kinase (AMPK) phosphorylation and nuclear human Forkhead box O1 (FOXO1) protein in estrogen‐dependent endometrial cancer (EC) tumors compared to normal control endometrium. Metformin treatment suppressed EC cell growth in a time‐dependent manner in vitro; this effect was cancelled by cotreatment with an AMPK inhibitor, compound C. Metformin decreased FOXO1 phosphorylation and increased FOXO1 nuclear localization in Ishikawa and HEC‐1B cells, with non‐significant increase in FOXO1 mRNA expression. Moreover, compound C blocked the metformin‐induced changes of FOXO1 and its phosphorylation protein, suggesting that metformin upregulated FOXO1 activity by AMPK activation. Similar results were obtained after treatment with insulin. In addition, transfection with siRNA for FOXO1 cancelled metformin‐inhibited cell growth, indicating that FOXO1 mediated metformin to inhibit EC cell proliferation. A xenograft mouse model further revealed that metformin suppressed HEC‐1B tumor growth, accompanied by downregulated ki‐67 and upregulated AMPK phosphorylation and nuclear FOXO1 protein. Taken together, these data provide a novel mechanism of antineoplastic effect for metformin through the regulation of FOXO1, and suggest that the AMPK–FOXO1 pathway may be a therapeutic target to the development of new antineoplastic drugs.

CD36 plays a negative role in the regulation of lipophagy in hepatocytes through an AMPK-dependent pathway

“…FOXO1 is also largely known as an important transcription factor to induce autophagy (38). The activation of AMPK can regulate the activation of FOXO1 (39,40). However, our results reveal that CD36 knockdown in HepG2 cells reduces the mRNA and protein expression of FOXO1 but increases the level of p-FOXO1.…”

“…However, our results reveal that CD36 knockdown in HepG2 cells reduces the mRNA and protein expression of FOXO1 but increases the level of p-FOXO1. Several studies have reported that cytoplasmic p-FOXO1 is inactivated (37,39). However, Wang et al (41) noted that p-FOXO1 is located in the cytoplasm of iNKs and interacts with ATG7, leading to the induction of autophagy, which was independent of the transcriptional activity of FOXO1.…”

FOXO1 Inhibits Tumor Cell Migration via Regulating Cell Surface Morphology in Non-Small Cell Lung Cancer Cells

“…FOXO1 proteins are regulated by phosphorylation, ubiquitination, and acetylation via several kinases [25]. By contrast, AMPPK and JNK were suggested to induce nuclear translocation and activation of FOXO1 proteins [26]. In addition, FOXO transcription factors regulate different cellular processes, such as inhibition of proliferation, induction of differentiation or apoptosis, and protection against oxidative damage.…”

Synergistic effect of metformin and medroxyprogesterone 17‑acetate on the development of endometrial cancer

“…Metformin is a common insulin-sensitizing agent used to treat type II diabetes. However, accumulating evidence indicated that metformin could be applied in the treatment of some malignant diseases including EC (28)(29)(30). Firstly, as an insulin-sensitizing agent, metformin decreased the circulating insulin levels by inhibiting the hepatic glucose and lipid synthesis, as well as by increasing muscle glucose uptake.…”