The effect of eIF3a on anthracycline-based chemotherapy resistance by regulating DSB DNA repair

Release time:2023-02-01

Impact Factor:6.1

DOI number:10.1016/j.bcp.2021.114616

Affiliation of Author(s):Xiangya Hospital, Central South University

Teaching and Research Group:Department of Clinical Pharmacology

Journal:Biochemical pharmacology

Place of Publication:England

Funded by:国家自然科学基金项目

Key Words:Keywords: Anthracycline; Breast cancer; Chemotherapy resistance; DNA repair; eIF3a.

Abstract:Background: Anthracycline are inhibitors of topoisomerase II leading to DNA double strand breaks, and it is widely used for treatment of breast cancer. eIF3a is the largest subunit of eukaryotic translation initiation factor 3 (eIF3) and highly expressed in breast cancer. In this study, we investigated the role of eIF3a in DSB DNA repair and the response of breast cancer patients to anthracycline-based chemotherapy. Methods: MTT assay was used to detect anthracycline sensitivity in cell lines. Real-time reverse transcriptase PCR, western blotting and immunofluorescence were performed to assess changes in gene expression levels. Cometassay and end-joining activity assay were conducted to explore the effect of eIF3a in NHEJ repair. Luciferase reporter assay was performed to detect LIG4 5'UTR activity. Immunohistochemistry was used to detect eIF3a, LIG4 and DNA-PKcs expression levels in breast cancer tissues. Results: The results showed that eIF3a increased cellular response to anthracyclines by regulating DSB repair activity via influencing the expression of LIG4 and DNA-PKcs at translational level. Breast cancer patients with high level of eIF3a or low level of LIG4 or low level of DNA-PKcs had better anthracycline-based chemotherapy prognosis compared. Moreover, Combined expressions of eIF3a, LIG4 and DNA-PKcs could be better to predict PFS in breast cancer patients with anthracycline-based chemotherapy. Conclusion: Our findings suggest that eIF3a effects anthracycline-based chemotherapy response by regulating DSB DNA repair.

Co-author:Zi-Zheng Dong, Ting Zou, Zhan Wang, Yao Shen, Wei Zhuo, Xiang-Ping Li, Di Xiao, Hai-Tao Liu, Xiang Chen, Hong-HaoZhou

First Author:Juan Chen, Jun-Yan Liu

Indexed by:Article

Correspondence Author:Zhao-Qian Liu, Jian-Ting Zhang, Ji-Ye Yin

Discipline:Medicine

First-Level Discipline:Pharmaceutical Science

Document Type:J

Volume:190

Page Number:114616

ISSN No.:0006-2952

Translation or Not:no

Date of Publication:2021-05-17

Included Journals:SCI

Links to published journals:https://www.sciencedirect.com/science/article/abs/pii/S0006295221002227?via%3Dihub