Metformin inhibits the growth of ovarian cancer cells by promoting the Parkin-induced p53 ubiquitination.

Xiaojia Min,Tingting Zhang,Ying Lin,Bo Wang,Kean Zhu

doi:10.1042/bsr20200679

Abstract

Ovarian cancer is the most lethal diseases among women. The chemo-resistance has been a big challenge for the cancer treatment. It has been reported that metformin may inhibit ovarian cancer and is able to impede the development of drug resistance, but the molecular mechanisms remain elusive. In this study, we explored the molecular roles of metformin in Parkin expression and p53 ubiquitination in chemo-resistant ovarian cancer cells. Firstly, ovarian cancer and chemo-resistant ovarian cancer cells were selected for determining the expression of Parkin, p53, and p53 signaling pathway-related factors. Then the cell proliferation and viability after loss- and gain-of-function assays were measured. Besides, immunoprecipitation (IP) was used to determine the interactions between Parkin and p53, and the ubiquitination level of p53 was measured using in vitro ubiquitination assay. Finally, the degradation of p53 proteasome regulated by Parkin was monitored using the MG132 proteasome inhibitor. We found that metformin significantly inhibited the growth of ovarian cancer parental cells and chemo-resistant cells, and metformin promoted Parkin expression in chemo-resistant cells. Further, up-regulated Parkin expression promoted the ubiquitination and degradation of p53, and metformin inhibited the expression of p53 to suppress the proliferation of chemo-resistant ovarian cancer cells. Mechanistically, metformin could inhibit the growth of ovarian cancer cells by promoting the Parkin-induced p53 ubiquitination. Altogether, our study demonstrated an inhibitory role of metformin in the growth of chemo-resistant cancer cells through promoting the Parkin-induced p53 ubiquitination, which provides a novel mechanism of metformin for treating ovarian cancer.

Highlights

Ovarian cancer is one of the most prevalent gynecological malignant tumors [1]
Metformin inhibits the growth of ovarian cancer parental cells and chemo-resistant cells In order to explore the effect of metformin on the chemo-resistance of ovarian cancer cells, the ovarian cancer parental cells A2780 and IGROV1 and chemo-resistant cell A2780-cis, IGROV1-cis were treated with different concentrations (0, 5, 10, 20 mM) of metformin, respectively
The expression of Parkin increased after treating with 20 mM metformin and 10 μM MG132, which promoted the ubiquitination and degradation of p53 (Figure 3E). These results suggested that the ubiquitination of p53 was mediated by Parkin in ovarian cancer chemo-resistant cells, and the degradation of p53 was promoted by metformin

Summary

Introduction

Ovarian cancer is one of the most prevalent gynecological malignant tumors [1]. The incidence of ovarian cancer differs among countries: the highest incidence rates are shown in the developed regions, while the lowest rates observed in African and Asian parts [2]. Increasing number of patients with relapse in one to two years under different circumstances gradually develop resistance to the chemotherapies [4]. It is urgent to explore the underlying molecular mechanisms of progression of chemo-resistance of ovarian cancer and to identify novel targets for the therapy of ovarian cancer. A study has indicated that metformin may have an anti-cancer effect on ovarian cancer through inhibition of the ovarian cancer cell proliferation [5]

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Conclusion