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.
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Research Article|
September 01 2020
Metformin inhibits the growth of ovarian cancer cells by promoting the Parkin-induced p53 ubiquitination
Xiaojia Min;
Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, China
* Corresponding Author; email: minxiaojia@hunnu.edu.cn
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Tingting Zhang;
Tingting Zhang
The Second Xiangya Hospital of Central South University, Changsha, China
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Ying Lin;
Ying Lin
Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, China
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Bo Wang;
Bo Wang
Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, China
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Kean Zhu
Kean Zhu
Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, China
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Publisher: Portland Press Ltd
Received:
March 06 2020
Revision Received:
June 24 2020
Accepted:
July 13 2020
Online ISSN: 1573-4935
Print ISSN: 0144-8463
Copyright 2020 The Author(s)
2020
This is an Accepted Manuscript; not the final Version of Record. You are encouraged to use the final Version of Record that, when published, will replace this manuscript and be freely available under a Creative Commons licence.
Biosci Rep (2020) BSR20200679.
Article history
Received:
March 06 2020
Revision Received:
June 24 2020
Accepted:
July 13 2020
Citation
Xiaojia Min, Tingting Zhang, Ying Lin, Bo Wang, Kean Zhu; Metformin inhibits the growth of ovarian cancer cells by promoting the Parkin-induced p53 ubiquitination. Biosci Rep 2020; BSR20200679. doi: https://doi.org/10.1042/BSR20200679
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