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Metformin regulation of progesterone receptor isoform-B expression in human endometrial cancer cells is
Sofia Jade U Saguyod1, Iad Alhallak2, Rosalia C M Simmen2,3
1Institute of Biology, College of Science, University of the Philippines Diliman, Quezon City, PH 1101, Philippines.
Abstract:
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.
Insights
Metformin
Area of Science:
- Endocrinology
- Oncology
- Metabolism
Background:
- Metformin (MET) is a first-line treatment for type 2 diabetes.
- Insulin resistance is linked to increased cancer risk, suggesting MET's potential in cancer therapy.
- The precise anti-cancer mechanisms of MET, particularly its effects on progesterone receptor (PGR) expression in endometrial cancer (EC) under diabetic conditions, require further elucidation.
Purpose of the Study:
- To investigate the effects of MET on endometrial cancer (EC) cell proliferation and progesterone receptor (PGR) expression under normal and high glucose conditions simulating diabetes.
- To explore the role of glucose concentration in mediating MET's impact on EC cells.
- To elucidate the molecular mechanisms underlying MET's influence on PGR expression, including the involvement of AMPK signaling.
Main Methods:
- Ishikawa EC cells were treated with 17β-estradiol (E2) and/or MET under normal (5.5 mM) and high (17.5 mM) glucose concentrations.
- Cell proliferation, spheroid formation, and PGR (total, PGR-A, PGR-B) transcript levels were assessed.
- Experiments involved gene silencing (siRNA for Krüppel-like factor 9) and pharmacological modulators of AMPK signaling (Compound C, AICAR).
Main Results:
- Under normal glucose, MET reduced E2-induced proliferation and cyclin D1 expression, while increasing total PGR and PGR-B transcripts.
- MET's effect on spheroid formation was observed only without E2.
- Under high glucose, MET did not affect proliferation or spheroid formation in E2-treated cells, but increased total PGR transcripts (not PGR-B).
- AMPK activation (AICAR) increased PGR-B, while AMPK inhibition (Compound C) abrogated MET's effect on PGR-B, suggesting AMPK involvement.
Conclusions:
- Metformin's effects on endometrial cancer cells, particularly PGR-B isoform expression, are glucose-dependent.
- These findings highlight the complex interplay between glucose metabolism, MET, and hormone receptor expression in EC.
- Understanding these glucose-dependent mechanisms may optimize progestin therapy for diabetic women with EC.
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