Role of metformin on cell proliferation and apoptosis in cervical cancer

Abstract

Aim: To examine the role of metformin in cervical cancer using in-vitro studies. Background: Cervical cancer is the fourth commonest gynaecological malignancy in the world. For those who have distant metastasis, the prognosis is poor. The mainstay treatment is chemotherapy with or without bevacizumab, as well as immune checkpoint inhibitor. However, the response rate remains poor. The aim of this study is to examine the role of metformin in cervical cancer. Methods: The in-vitro effects of metformin on the proliferation and apoptosis on cervical cancer and the underlying mechanisms were evaluated using two cell lines, SiHa and C4-I. Results: Metformin was able to suppress cell proliferation in both cervical cancer cell lines in a dose-dependent manner. Metformin inhibited IGF-1R expression especially in SiHa and in turn, it reduced the proliferative effect of AKT/mTOR and MEK/MAPK on cancer cells. It also activated AMPK to suppress the mTOR and p70S6K, leading to decrease of cell growth. Moreover, treatment of cancer cells with metformin induced apoptosis, which was likely due to the activation of the p38MAPK and JNK cascades. Similar actions of metformin were also observed in AMPK-silenced cells where the expression of cleaved PARP expression was induced, and the expression of total PARP, AKT, MEK1/2 and p44/42MAPK was reduced. All these suggested that metformin functioned through both AMPK-dependent and AMPK-independent pathways. Conclusion: Metformin inhibited cervical cancer cell proliferation and induced apoptosis through various cell signalling cascades, including inhibiting IGF-1R/AKT/mTOR and MEK/MAPK cascades, activation of AMPK, inhibition of mTOR, and activation of p38MAPK. Metformin may be useful as combined treatment in cervical cancer and further research is needed.