Metformin Modulates Cyclin D1 and P53 Expression to Inhibit Cell Proliferation and to Induce Apoptosis in Cervical Cancer Cell Lines

Document Type: Research Articles

Authors

1 Departement of Pharmacology, Faculty of Medicine, Sebelas Maret University, Surakarta, Indonesia.

2 Departement of Pharmacology, Faculty of Medicine, Gadjah Mada University, Yogyakarta, Indonesia.

3 Departement of Phisiology, Faculty of Medicine, Sebelas Maret University, Surakarta, Indonesia.

4 Departement of Anatomy, Faculty of Medicine, Sebelas Maret University, Surakarta, Indonesia.

Abstract

Background: Cervical cancer is one of the most prevalent gynecological cancers worldwide and contributes in high
mortality of Indonesian women. The efficacy of chemotherapy as a standart therapy for cervical cancer decreases because
it frequenly rises adverse effects. Recent studies have found that metformin has a potential anticancer effect mostly
through reduction of cyclin expression and activation of Activated Adenosine Monophosphate Kinase (AMPK). This
study aimed to investigate the effect of metfomin on expression of cyclin D1 and p53 and apoptosis in HeLa cancer cell
line. Methods: HeLa cells were treated with various doses of metformin and doxorubicin as a positive control. Cytotoxic
effect of metformin was determined using the MTT assay. Immunocytochemistry was used to assess cyclin D1 and p53
expression and apoptosis levels of treated HeLa cells were analyzed using flowcytometry. Data of cyclin D1 expression
was statistically analyzed using the Kruskal-Wallis test followed by the Tamhane test, whilst ANOVA and Tukey post
Hoc tests were used to analyze data of p53 and apoptosis level. The significant value was p< 0.05. Results: Metformin
was able to inhibit proliferation of HeLa cells with IC50 60 mM. HeLa cells treated with 60 and 120 mM metformin
had lower cyclin D1 expression than HeLa cells treated without metformin and reached a significant difference (p=
0.001). Moreover, 30 mM or higher doses of metformin increase significantly p53 expression (p< 0.001). Induction of
apoptosis was observed in HeLa cells treated with all doses of metformin and reached statistically difference (p= 0.04
and p < 0.001). Conclusion: Metformin can modulate cyclin D1 and p53 expression in HeLa cancer cell line, leading
to inhibition of cell proliferation and induction of apoptosis. Other cyclin family members, CDK inhibitors and AMPK
signaling should be further investigated in order to know mechanism of metformin action.

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