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Metformin attenuates ovarian cancer cell growth in an AMP-kinase dispensable manner.

Rattan R, Giri S, Hartmann LC, Shridhar V - J. Cell. Mol. Med. (2011)

Bottom Line: Metformin, the most widely used drug for type 2 diabetes activates 59 adenosine monophosphate (AMP)-activated protein kinase (AMPK), which regulates cellular energy metabolism.We also show that metformin-mediated effect on AMPK is dependent on liver kinase B1 (LKB1) as it failed to activate AMPK-ACC pathway and cell cycle arrest in LKB1 mouse embryo fibroblasts (mefs).Collectively, these results provide evidence on the role of metformin as an anti-proliferative therapeutic that can act through both AMPK-dependent as well as AMPK-independent pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Pathology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN 55905, USA.

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Metformin causes cell cycle arrest in G1-phase. (A) A2780, CP70, C200 and SKOV3ip cells were treated with metformin with indicated concentrations for 24 hrs. Cells were fixed overnight, stained with propidium iodide and flow-sorted. The data represent three separate experiments. ***P < 0.001; **P < 0.01, *P < 0.05; NS: not significant compared to untreated cells. (B) Immunoblot analysis of ovarian cancer cells treated with metformin showing reduced cyclin D1 and up-regulated p21 levels. Blots are representation of two separate experiments.
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fig03: Metformin causes cell cycle arrest in G1-phase. (A) A2780, CP70, C200 and SKOV3ip cells were treated with metformin with indicated concentrations for 24 hrs. Cells were fixed overnight, stained with propidium iodide and flow-sorted. The data represent three separate experiments. ***P < 0.001; **P < 0.01, *P < 0.05; NS: not significant compared to untreated cells. (B) Immunoblot analysis of ovarian cancer cells treated with metformin showing reduced cyclin D1 and up-regulated p21 levels. Blots are representation of two separate experiments.

Mentions: To determine if metformin-mediated inhibition of cell proliferation may reflect changes in cell cycle, we examined cell cycle distribution by flow cytometry. As depicted in Fig. 3A, metformin treatment led to accumulation of cells in G1-phase with corresponding decrease in the percentage of cells in the S-phase in all ovarian cancer cell lines tested compared to untreated cells. Consistent with this G1 arrest, immunoblot analysis revealed that metformin treatment resulted in reduced cyclin D1 levels with concomitant increase in the expression of p21 in A2780, CP70, C200 and SKOV3ip cells; however, there was no change in the expression of p27 (Fig. 3B). Densitometric representation of the data is shown in Fig. S2. Collectively, these results suggest that metformin inhibits cell cycle progression by modulating the expression of cell cycle proteins.


Metformin attenuates ovarian cancer cell growth in an AMP-kinase dispensable manner.

Rattan R, Giri S, Hartmann LC, Shridhar V - J. Cell. Mol. Med. (2011)

Metformin causes cell cycle arrest in G1-phase. (A) A2780, CP70, C200 and SKOV3ip cells were treated with metformin with indicated concentrations for 24 hrs. Cells were fixed overnight, stained with propidium iodide and flow-sorted. The data represent three separate experiments. ***P < 0.001; **P < 0.01, *P < 0.05; NS: not significant compared to untreated cells. (B) Immunoblot analysis of ovarian cancer cells treated with metformin showing reduced cyclin D1 and up-regulated p21 levels. Blots are representation of two separate experiments.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3822503&req=5

fig03: Metformin causes cell cycle arrest in G1-phase. (A) A2780, CP70, C200 and SKOV3ip cells were treated with metformin with indicated concentrations for 24 hrs. Cells were fixed overnight, stained with propidium iodide and flow-sorted. The data represent three separate experiments. ***P < 0.001; **P < 0.01, *P < 0.05; NS: not significant compared to untreated cells. (B) Immunoblot analysis of ovarian cancer cells treated with metformin showing reduced cyclin D1 and up-regulated p21 levels. Blots are representation of two separate experiments.
Mentions: To determine if metformin-mediated inhibition of cell proliferation may reflect changes in cell cycle, we examined cell cycle distribution by flow cytometry. As depicted in Fig. 3A, metformin treatment led to accumulation of cells in G1-phase with corresponding decrease in the percentage of cells in the S-phase in all ovarian cancer cell lines tested compared to untreated cells. Consistent with this G1 arrest, immunoblot analysis revealed that metformin treatment resulted in reduced cyclin D1 levels with concomitant increase in the expression of p21 in A2780, CP70, C200 and SKOV3ip cells; however, there was no change in the expression of p27 (Fig. 3B). Densitometric representation of the data is shown in Fig. S2. Collectively, these results suggest that metformin inhibits cell cycle progression by modulating the expression of cell cycle proteins.

Bottom Line: Metformin, the most widely used drug for type 2 diabetes activates 59 adenosine monophosphate (AMP)-activated protein kinase (AMPK), which regulates cellular energy metabolism.We also show that metformin-mediated effect on AMPK is dependent on liver kinase B1 (LKB1) as it failed to activate AMPK-ACC pathway and cell cycle arrest in LKB1 mouse embryo fibroblasts (mefs).Collectively, these results provide evidence on the role of metformin as an anti-proliferative therapeutic that can act through both AMPK-dependent as well as AMPK-independent pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Pathology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN 55905, USA.

Show MeSH
Related in: MedlinePlus