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Published on: August 23, 2019
Metformin inhibits cervical cancer cell proliferation via decreased AMPK O-GlcNAcylation
Min Young Kim1, Yoon Sook Kim1, Minjun Kim1
1Gyeongsang National University, Jinju, The Republic of Korea.
Abstract:
Metformin is a widely used drug for the treatment of type 2 diabetes. Antidiabetic drugs are also known to influence cancer progression, as high glucose levels affect both cancer and diabetes. Metformin induces cell cycle arrest in cancer cells, but the underlying mechanism remains unclear in cervical cancer system. Here, we examined how metformin affects cell cycle arrest and apoptosis in cervical cancer cells. Western blot analysis showed that levels of O-linked N-acetylglucosamine (O-GlcNAc) and O-GlcNAc transferase (OGT) were increased in cervical cancer cells; these effects were reversed by metformin treatment. Immunoprecipitation analysis was used to examine the interplay between O-GlcNAcylation and phosphorylation in HeLa cells, revealing that metformin decreased O-GlcNAcylated AMP-activated protein kinase (AMPK) and increased levels of phospho-AMPK compared to untreated cells. These results were associated with decreased cell cycle arrest and apoptotic cell death in HeLa cells, as shown by flow cytometry. Moreover, 6-diazo-5-oxo-L-norleucine (a glutamine fructose-6-phosphate aminotransferase inhibitor) or thiamet G (an O-GlcNAcase inhibitor) decreased or increased levels of O-GlcNAcylated AMPK, and increased or decreased levels of phosphorylated AMPK, respectively, suggesting that O-GlcNAc modification affects AMPK activation. Of note, we found that metformin treatment of HeLa cells increased the levels of p21 and p27 (which are AMPK-dependent cell cycle inhibitors), leading to increased cell cycle arrest and apoptosis in HeLa cells compared to untreated cells. These findings suggest that metformin may serve as a useful antiproliferative drug in cervical cancer cells, with potential therapeutic benefit.
Insights
Metformin treatment reversed increased O-linked N-acetylglucosamine (O-GlcNAc) levels in cervical cancer cells. This led to increased cell cycle arrest and apoptosis, suggesting metformin
Area of Science:
- Oncology
- Endocrinology
- Biochemistry
Background:
- Metformin, a type 2 diabetes drug, influences cancer progression due to the link between high glucose levels and both conditions.
- The precise mechanism by which metformin induces cell cycle arrest in cervical cancer remains incompletely understood.
Purpose of the Study:
- To investigate the effects of metformin on cell cycle arrest and apoptosis in cervical cancer cells.
- To elucidate the role of O-linked N-acetylglucosamine (O-GlcNAc) modification and AMP-activated protein kinase (AMPK) signaling in metformin's action.
Main Methods:
- Western blot analysis to quantify O-GlcNAc, O-GlcNAc transferase (OGT), and phosphorylated AMP-activated protein kinase (p-AMPK) levels.
- Immunoprecipitation to assess the interaction between O-GlcNAcylation and phosphorylation.
- Flow cytometry to determine cell cycle arrest and apoptotic cell death.
- Treatment with specific enzyme inhibitors (6-diazo-5-oxo-L-norleucine and thiamet G) to probe O-GlcNAc modification pathways.
Main Results:
- Metformin treatment decreased elevated O-linked N-acetylglucosamine (O-GlcNAc) and O-GlcNAc transferase (OGT) levels in cervical cancer cells.
- Metformin reduced O-GlcNAcylated AMP-activated protein kinase (AMPK) and increased phosphorylated AMPK (p-AMPK) levels.
- Metformin treatment increased the expression of cell cycle inhibitors p21 and p27, leading to enhanced cell cycle arrest and apoptosis.
Conclusions:
- O-GlcNAc modification plays a role in regulating AMPK activation in cervical cancer cells.
- Metformin's antiproliferative effects in cervical cancer are mediated through modulation of O-GlcNAc levels and subsequent induction of cell cycle arrest and apoptosis.
- Metformin demonstrates potential as a therapeutic agent for cervical cancer treatment.
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