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Peptidylarginine deiminase 4 overexpression resensitizes MCF-7/ADR breast cancer cells to adriamycin via GSK3β/p53 activation

Authors Zhou Q, Song C, Liu X, Qin H, Miao L, Zhang X

Received 18 October 2018

Accepted for publication 10 December 2018

Published 10 January 2019 Volume 2019:11 Pages 625—636

DOI https://doi.org/10.2147/CMAR.S191353

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Cristina Weinberg

Peer reviewer comments 2

Editor who approved publication: Dr Antonella D'Anneo


Qianqian Zhou,1,* Chao Song,1,* Xiaoqiu Liu,2,3,* Hao Qin,1 Lixia Miao,1 Xuesen Zhang1

1State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China; 2Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, China; 3Department of Microbiology, Nanjing Medical University, Nanjing, China

*These authors contributed equally to this work

Background: Adriamycin (ADR) is widely used in the clinical chemotherapy against breast cancer. But its efficacy is strongly limited due to the acquisition of multidrug resistance (MDR). Therefore, acquisition of the resistance to ADR is still a major cause of chemotherapy failure in breast cancer patients. Peptidylarginine deiminase IV (PAD4) is reported to target non-histone proteins for citrullination, regulate their substrate activities, and thereby play critical roles in maintaining cell phenotype in breast cancer cells. However, whether PAD4 is involved in the development of MDR in breast cancer is poorly understood.
Materials and methods: We examined the expression of PAD family members, including PAD4 in ADR-resistant MCF-7 cells compared with the parental control cells by real-time PCR and Western blotting analyses. Rescue of PAD4 expression in MCF-7/ADR cells was performed to assess whether PAD4 could restore the sensitivity of MCF-7/ADR cells to ADR treatment with cell counting kit-8, flow cytometry, TUNEL, nuclear and cytoplasmic extract preparations, and immunofluorescence staining analyses.
Results: Both PAD2 and PAD4 were significantly decreased in ADR-resistant cells. However, only PAD4 overexpression can increase the sensitivity of MCF-7/ADR cells to ADR treatment and decrease MDR1 gene expression. Overexpression of PAD4 in MCF-7/ADR cells inhibited cell proliferation by inducing cell apoptosis. Under ADR treatment, overexpression of PAD4 promoted nuclear accumulation of glycogen synthase kinase-3β and p53, which further activated proapoptotic gene expression and downregulated MDR1 expression. Moreover, PAD4 activity was required for activating proapoptotic gene transcripts.
Conclusion: We demonstrate the previously unappreciated role of PAD4 in reversing ADR resistance in MCF-7/ADR cells and help establish PAD4 as a candidate biomarker of prognosis and chemotherapy target for MDR in breast cancers.

Keywords: PAD4, apoptosis, MDR, breast cancer, GSK3β

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