Metformin promotes apoptosis in primary breast cancer cells by downregulation of cyclin D1 and upregulation of P53 through an AMPK-alpha independent mechanism

Authors: GÜVEN YENMİŞ, NAİL BEŞLİ, ELİF YAPRAK SARAÇ, FATMA SİNEM HOCAOĞLU EMRE, KAZIM ŞENOL, GÖNÜL KANIGÜR

Abstract: Background/aim: In the present study we aimed to figure out the effect of metformin on the expression of AMPK-alpha, cyclin D1, and Tp53, and apoptosis in primary breast cancer cells (PBCCs). Materials and methods: PBCCs were treated with two doses of metformin (0 mM, 25 mM). Proliferation was determined by BrdU assay. Real-time PCR was used to assess AMPK-alpha, cyclin D1, and Tp53 gene expressions; apoptotic indexes of PBCCs were analyzed using flow-cytometry. Results: Twenty-four-hour incubation with 25 mM metformin reduced the proliferation of PBCCs. AMPK-alpha gene expression in PBCCs was not affected by 25 mM metformin treatment compared with the control group. PBCCs treated with 25 mM metformin had lower cyclin D1 expression compared with nontreated cells; however, the difference was not statistically significant. Twenty-five millimolar dose of metformin increased p53 expression significantly compared with the nontreated group. The high concentration of metformin elevated the number of annexin V-positive apoptotic cells, and the increase in the apoptotic index was statistically significant. Conclusion: Metformin can modulate cyclin D1 and p53 expression through AMPK-alpha-independent mechanism in breast cancer cells, leading to cell proliferation inhibition and apoptosis induction.

Keywords: AMPK-alpha, cyclin D1, Tp53, breast cancer, metformin

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