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.

Highlights

  • The failure of cancer chemotherapy is mostly caused by the development of drug resistance

  • To detect the expression of CRL4 in ovarian cancer, we examined the levels of CRL4 (Cul4A and DDB1) E3 ligase in ovarian cancer tissues and normal interstitial tissues

  • IHC staining of the tissue microarray (TMA) slide showed that Cul4A was expressed in both cytoplasm and nucleus, and that the positive expression rate of Cul4A in ovarian tumor tissues (67.6%, 48/71 cases) was higher than that in normal interstitial tissue (26.7%, 4/15 cases), indicating that Cul4A was overexpressed in ovarian tumor tissue (Fig. 1b)

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Summary

Introduction

The failure of cancer chemotherapy is mostly caused by the development of drug resistance. In addition to the extensive genetic and epigenetic alterations in cancer cells, cancer cell heterogeneity and mutations in drug targets may contribute to increased drug resistance. Research that aims to provide a better understanding on the mechanism of chemoresistance would benefit the development of more effective personalized treatment strategies. Cisplatin and its derivatives are known to be frontline drugs in treating a number of solid tumors. Cullin-RING ubiquitin ligases (CRLs), the largest family of E3 ligases, play a pivotal role in the regulation of cell cycle progression, nucleosome assembly during DNA replication, genomic stability maintenance, and other important physiological events[1]. Overexpression of CRL4, Official journal of the Cell Death Differentiation Association

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