Metformin Induces G1 Cell Cycle Arrest and Inhibits Cell Proliferation in Nasopharyngeal Carcinoma Cells

Abstract

It has been reported that metformin, a biguanide derivative widely used in type II diabetic patients, has antitumor activities in some cancers by activation of AMP-activated protein kinase (AMPK). But its role in nasopharyngeal carcinoma (NPC) is not known. Here, we reported for the first time that 1-50 mM of metformin in a dose-and time-dependent manner suppressed cell proliferation and colony formation in NPC cell line, C666-1. Further studies revealed that the protein level of cyclin D1 decreased and the percentage of the cells in G0/G1 phase increased by 5 mM metformin treatment. Metformin also induced the phosphorylation of AMPK (T172) in a time-dependent manner. Mammalian target of rapamycin complex 1 (mTORC1), which is negatively regulated by AMPK and plays a central role in cell growth and proliferation, was inhibited by metformin, as manifested by dephosphorylation of its downstream targets 40S ribosomal S6 kinase 1 (S6K1) (T389), the eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) (T37/46) and S6 (S235/236) in C666-1 cells. In a summary, metformin prevents proliferation of C666-1 cells by down-regulating cyclin D1 level and inducing G1 cell cycle arrest. AMPK-mediated inhibition of mTORC1 signaling may be involved in this process. Anat Rec, 294:1337Rec, 294: -1343Rec, 294: , 2011. V V C 2011 Wiley-Liss, Inc.

Metformin inhibits the prometastatic effect of sorafenib in hepatocellular carcinoma by upregulating the expression of TIP30

“…However, metformin's specific anticancer mechanism has not been clarified. Some studies suggest that metformin can activate the tumor suppressors in the AMPK metabolic pathway and prompt downstream factors such as mTOR, p53, and FOXO3 to adjust metabolism, growth rate, and the cell cycle . Our results confirmed that a combination of sorafenib and metformin upregulated the activity of AMPK and expression of TIP30.…”

Anti-tumor effects of metformin on head and neck carcinoma cell lines: A systematic review

“…Lin et al (8), Luo et al (38) and Sikka et al (39) demonstrated accumulation of cells in the G0/G1 phase when HNSCC cell lines were treated with metformin. Activation of AMPK and subsequent inhibition of mTORC1 signaling, reduction of cyclin D1 levels and dephosphorylation of AKT (at Ser473) have been shown to participate in metformin-induced apoptotic process (69). …”

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

“…In the present study, we have documented that metformin diminishes cyclin D1 expression, replenishes p53 expression and induces apoptosis in HeLa cells (Figure 1-3). Reduction of cyclin D1 expression is also found in nasopharyngeal cancer (C666-1), prostate cancer (LNCaP) and head and neck squamous cell carcinoma (FaDU and Detroit 562) incubated with 5-20 mM metformin for 72 h (Sahra et al, 2008;Zhao et al, 2011;Sikka et al, 2012). Another study shows that metformin plays an important role in global inhibition of protein translation, including cyclin D1 protein (Sikka et al, 2012).…”