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Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2023

Open Access 01-12-2023 | Ovarian Cancer | Research

A traditional gynecological medicine inhibits ovarian cancer progression and eliminates cancer stem cells via the LRPPRC–OXPHOS axis

Authors: Ruibin Jiang, Zhongjian Chen, Maowei Ni, Xia Li, Hangjie Ying, Jianguo Fen, Danying Wan, Chanjuan Peng, Wei Zhou, Linhui Gu

Published in: Journal of Translational Medicine | Issue 1/2023

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Abstract

Background

Ovarian cancer (OC) is the most lethal malignant gynecological tumor type for which limited therapeutic targets and drugs are available. Enhanced mitochondrial oxidative phosphorylation (OXPHOS), which enables cell growth, migration, and cancer stem cell maintenance, is a critical driver of disease progression and a potential intervention target of OC. However, the current OXPHOS intervention strategy mainly suppresses the activity of the electron transport chain directly and cannot effectively distinguish normal tissues from cancer tissues, resulting in serious side effects and limited efficacy.

Methods

We screened natural product libraries to investigate potential anti-OC drugs that target OXPHOS. Additionally, LC-MS, qRT-PCR, western-blot, clonogenic assay, Immunohistochemistry, wound scratch assay, and xenograft model was applied to evaluate the anti-tumor mechanism of small molecules obtained by screening in OC.

Results

Gossypol acetic acid (GAA), a widely used gynecological medicine, was screened out from the drug library with the function of suppressing OXPHOS and OC progression by targeting the leucine-rich pentatricopeptide repeat containing (LRPPRC) protein. Mechanically, LRPPRC promotes the synthesis of OXPHOS subunits by binding to RNAs encoded by mitochondrial DNA. GAA binds to LRPPRC directly and induces LRPPRC rapid degradation in a ubiquitin-independent manner. LRPPRC was overexpressed in OC, which is highly correlated with the poor outcomes of OC and could promote the malignant phenotype of OC cells in vitro and in vivo. GAA management inhibits cell growth, clonal formation, and cancer stem cell maintenance in vitro, and suppresses subcutaneous graft tumor growth in vivo.

Conclusions

Our study identified a therapeutic target and provided a corresponding inhibitor for OXPHOS-based OC therapy. GAA inhibits OC progression by suppressing OXPHOS complex synthesis via targeting LRPPRC protein, supporting its potential utility as a natural therapeutic agent for ovarian cancer.
Appendix
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Metadata
Title
A traditional gynecological medicine inhibits ovarian cancer progression and eliminates cancer stem cells via the LRPPRC–OXPHOS axis
Authors
Ruibin Jiang
Zhongjian Chen
Maowei Ni
Xia Li
Hangjie Ying
Jianguo Fen
Danying Wan
Chanjuan Peng
Wei Zhou
Linhui Gu
Publication date
01-12-2023
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2023
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-023-04349-3

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