Cul4 E3 ubiquitin ligase regulates ovarian cancer drug resistance by targeting the antiapoptotic protein BIRC3.

Abstract

CRL4, a well-defined E3 ligase, has been reported to be upregulated and is proposed to be a potential drug target in ovarian cancers. However, the biological functions of CRL4 and the underlying mechanism regulating cancer chemoresistance are still largely elusive. Here, we show that CRL4 is considerably increased in cisplatin-resistant ovarian cancer cells, and CRL4 knockdown with shRNAs is able to reverse cisplatin-resistance of ovarian cancer cells. Moreover, CRL4 knockdown markedly inhibits the expression of BIRC3, one of the inhibitors of apoptosis proteins (IAPs). Besides, lower expression level of BIRC3 is associated with better prognosis of ovarian cancer patients, and BIRC3 knockdown in ovarian cancer cells can recover their sensitivity to cisplatin. More importantly, we demonstrate that CRL4 regulates BIRC3 expression by mediating the STAT3, but not the PI3K pathway. Therefore, our results identified CRL4 as an important factor in ovarian cancer chemoresistance, suggesting that CRL4 and BIRC3 may serve as novel therapeutic targets for relapsed patients after treatment with cisplatin and its derivative to overcome the bottle neck of ovarian cancer chemoresistance.

• Authors: Xiaoyan Hu, Yang Meng, Lian Xu, Lei Qiu, Mingtian Wei, Dan Su, Xu Qi, Ziqiang Wang, Shengyong Yang, Cong Liu, Junhong Han
• Journal: Cell death & disease (Cell Death Dis) Vol. 10 Issue 2 Pg. 104 (02 04 2019) ISSN: 2041-4889 [Electronic] England
• PMID: 30718461 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• CUL4A protein, human
• Cullin Proteins
• IL17RB protein, human
• STAT3 Transcription Factor
• STAT3 protein, human
• BIRC3 protein, human
• Baculoviral IAP Repeat-Containing 3 Protein
• Ubiquitin-Protein Ligases
• Cisplatin

Topics

• Apoptosis (drug effects, genetics)
• Apoptosis Regulatory Proteins (metabolism)
• Baculoviral IAP Repeat-Containing 3 Protein (genetics, metabolism)
• Cell Line, Tumor
• Cell Movement
• Cell Survival (drug effects)
• Cisplatin (pharmacology)
• Cullin Proteins (genetics, metabolism)
• Drug Resistance, Neoplasm (drug effects)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Ovarian Neoplasms (genetics, metabolism, mortality)
• Phosphatidylinositol 3-Kinases (metabolism)
• STAT3 Transcription Factor (genetics, metabolism)
• Ubiquitin-Protein Ligases (genetics, metabolism)