Targeting RNF8 effectively reverses cisplatin and doxorubicin resistance in endometrial cancer.

Abstract

BACKGROUND:

Endometrial cancer (EC) is one of the most frequent gynecological malignancy worldwide. However, resistance to chemotherapy remains one of the major difficulties in the treatment of EC. Thus, there is an urgent requirement to understand mechanisms of chemoresistance and identify novel regimens for patients with EC. We found that protein and mRNA expression levels of RNF8 were significantly increased in both cisplatin and doxorubicin resistant EC cells. Cell survival assay showed that RNF deficiency significantly enhanced the sensitivity of resistant EC cells to cisplatin and doxorubicin (P < 0.01). In addition, chemoresistant EC cells exhibited increased NHEJ efficiency. Knockout of RNF8 in chemoresistant EC cells significantly reduced NHEJ efficiency and prolonged Ku80 retention on DSB. Moreover, cisplatin resistant AN3CA xenograft showed that RNF8 deficiency overcame cisplatin resistance. Our in vitro and in vivo assays provide evidence for RNF8, which is a NHEJ factor, serving as a promising, novel target in EC chemotherapy.

• Authors: Ben Yang, Wang Ke, Yingchun Wan, Tao Li
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 545 Pg. 89-97 (03 19 2021) ISSN: 1090-2104 [Electronic] United States
• PMID: 33548629 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• DNA-Binding Proteins
• RNF8 protein, human
• Doxorubicin
• Ubiquitin-Protein Ligases
• Cisplatin

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Cisplatin (pharmacology)
• DNA End-Joining Repair
• DNA-Binding Proteins (antagonists & inhibitors, genetics)
• Doxorubicin (pharmacology)
• Drug Resistance, Neoplasm (physiology)
• Endometrial Neoplasms (drug therapy, genetics, metabolism)
• Female
• Gene Knockout Techniques
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Ubiquitin-Protein Ligases (antagonists & inhibitors, genetics)
• Xenograft Model Antitumor Assays