Metformin (MET) constitutes the first-line treatment against type 2 diabetes. Growing evidence linking insulin resistance and cancer risk has expanded the therapeutic potential of MET to several cancer types. However, the oncostatic mechanisms of MET are not well understood. MET has been shown to promote the expression of progesterone receptor (PGR) and other antitumor biomarkers in patients with non-diabetic endometrial cancer (EC) and in Ishikawa EC cells cultured in normal glucose (5.5 mM) media. Therefore, the present study aimed to assess the effects of MET on EC cells under conditions simulating diabetes. Ishikawa cells treated with 10 nM 17β-estradiol (E2) and/or 100 µM MET and exposed to normal and high (17.5 mM) concentrations of glucose were evaluated for proliferative and PGR expression status. Under normal glucose conditions, MET attenuated E2-induced cell proliferation and cyclin D1 gene expression, and increased total PGR and PGR-B transcript levels. MET inhibited Ishikawa cell spheroid formation only in the absence of E2 treatment. In E2-treated cells under high glucose conditions, MET showed no effects on cell proliferation and spheroid formation, and increased total PGR but not PGR-B transcript levels. Transfection with Krüppel-like factor 9 small interfering RNA increased PGR-A transcript levels, irrespective of glucose environment. Medroxyprogesterone acetate downregulated PGR-A expression more effectively with metformin under high compared with normal glucose conditions. To evaluate the potential mechanisms underlying the targeting of PGR by MET, E2-treated cells were incubated with MET and the AMPK inhibitor Compound C, or with the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), under normal glucose conditions. Compound C abrogated the effects of MET on PGR-B while AICAR increased PGR-B transcript levels, albeit less effectively compared with MET. The present results demonstrate the glucose-dependent effects of MET on PGR-B isoform expression, which may inform the response to progestin therapy in diabetic women with EC.
Keywords: AMP-activated protein kinase; Ishikawa cells; PGR; estrogen; metformin.
Copyright: © Saguyod et al.