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

• Published in: Journal of translational medicine Vol. 21; no. 1; p. 504
• Main Authors: Jiang, Ruibin, Chen, Zhongjian, Ni, Maowei, Li, Xia, Ying, Hangjie, Fen, Jianguo, Wan, Danying, Peng, Chanjuan, Zhou, Wei, Gu, Linhui
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 26-07-2023; BioMed Central; BMC
• Subjects: Acetic acid; Analysis; Animals; Bioenergetics; Cancer; Cancer therapies; Care and treatment; Cell culture; Cell growth; Cell Line, Tumor; Cell migration; Cell Proliferation; Chemotherapy; Development and progression; Disease Models, Animal; Drug development; Drugs; Electron transport; Electron transport chain; Female; Glucose; Gossypol; Gossypol acetic acid; Health aspects; Humans; Immunohistochemistry; Immunosuppressive agents; LRPPRC; Metabolism; Metabolites; Mitochondria - metabolism; Mitochondrial DNA; Natural products; Neoplasm Proteins - metabolism; Neoplastic Stem Cells - metabolism; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Oxidative Phosphorylation; Patient outcomes; Patients; Phenotypes; Phosphorylation; Protein biosynthesis; Proteins; Stem cells; Therapeutic applications; Therapeutic targets; Transplantation; Tumors; Ubiquitin; China; United States > US; California; Gossypol acetic acid; Oxidative phosphorylation; LRPPRC; Ovarian cancer
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/s12967-023-04349-3

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.
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.
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.
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.