Peroxiredoxin IV plays a critical role in cancer cell growth and radioresistance through the activation of the Akt/GSK3 signaling pathways

Na Ding, Hong Jiang, Pratik Thapa, Yanning Hao, Aziza Alshahrani, Derek Allison, Tadahide Izumi, Vivek M. Rangnekar, Xiaoqi Liu, Qiou Wei

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

High levels of redox enzymes have been commonly observed in various types of human cancer, although whether and how the enzymes contribute to cancer malignancy and therapeutic resistance have yet to be understood. Peroxiredoxin IV (Prx4) is an antioxidant with bona fide peroxidase and molecular chaperone functions. Here, we report that Prx4 is highly expressed in prostate cancer patient specimens, as well as established prostate cancer cell lines, and that its levels can be further stimulated through the activation of androgen receptor signaling. We used lentivirus-mediated shRNA knockdown and CRISPR-Cas9 based KO techniques to establish Prx4-depleted prostate cancer cells, which showed delayed cell cycle progression, reduced rate of cell proliferation, migration, and invasion compared to control cells. In addition, we used proteome profiler phosphokinase arrays to identify signaling changes in Prx4-depleted cells; we found that loss of Prx4 results in insufficient phosphorylation of both Akt and its downstream kinase GSK3α/β. Moreover, we demonstrate that Prx4-depleted cells are more sensitive to ionizing radiation as they display compromised ability to scavenge reactive oxygen species and increased accumulation of DNA damage. In mouse xenograft models, we show depletion of Prx4 leads to significant suppression of tumor growth, and tumors formed by Prx4-depleted cells respond more effectively to radiation therapy. Our findings suggest that increased levels of Prx4 contribute to the malignancy and radioresistance of prostate cancer through the activation of Akt/GSK3 signaling pathways. Therefore, strategies targeting Prx4 may be utilized to potentially inhibit tumor growth and overcome radioresistance in prostate cancer.

Original languageEnglish
Article number102123
JournalJournal of Biological Chemistry
Volume298
Issue number7
DOIs
StatePublished - Jul 2022

Bibliographical note

Funding Information:
The research is partially funded by a pilot award of the Prostate Expertise in Research for Overcoming Resistance and Mentoring (PERFORM) Alliance supported through the VPR office of the University of Kentucky . Some reagents and material used in this study were also generated through the support of other grant agencies including National Institutes of Health ( NCI grant number R01CA222596 ), Department of Defense (grant number W81XWH-16-1-0203 ), American Cancer Society (grant number RSG-16-213-01-TBE ), and Kentucky Lung Cancer Research Program ( KLCRP2016 ). This research was also supported by the Biostatistics and Bioinformatics, Oncogenomics, Biospecimen Procurement and Translational Pathology Shared Resource Facilities of the University of Kentucky Markey Cancer Center ( P30CA177558 ).

Publisher Copyright:
© 2022 The Authors

Keywords

  • antioxidant
  • peroxiredoxin
  • prostate cancer
  • radioresistance

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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