Repurposing an antidandruff agent to treating cancer: Zinc pyrithione inhibits tumor growth via targeting proteasome-associated deubiquitinases

Chong Zhao, Xin Chen, Changshan Yang, Dan Zang, Xiaoying Lan, Siyan Liao, Peiquan Zhang, Jinjie Wu, Xiaofen Li, Ningning Liu, Yuning Liao, Hongbiao Huang, Xianping Shi, Lili Jiang, Xiuhua Liu, Q. Ping Dou, Xuejun Wang, Jinbao Liu

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

The ubiquitin-proteasome system (UPS) plays a central role in various cellular processes through selectively degrading proteins involved in critical cellular functions. Targeting UPS has been validated as a novel strategy for treating human cancer, as inhibitors of the 20S proteasome catalytic activity are currently in clinical use for treatment of multiple myeloma and other cancers, and the deubiquitinase activity associated with the proteasome is also a valid target for anticancer agents. Recent studies suggested that zinc pyrithione, an FDA-approved antidandruff agent, may have antitumor activity, but the detailed molecular mechanisms remain unclear. Here we report that zinc pyrithione (ZnPT) targets the proteasome-associated DUBs (USP14 and UCHL5) and inhibits their activities, resulting in a rapid accumulation of protein-ubiquitin conjugates, but without inhibiting the proteolytic activities of 20S proteasomes. Furthermore, ZnPT exhibits cytotoxic effects against various cancer cell lines in vitro, selectively kills bone marrow cells from leukemia patients ex vivo, and efficiently inhibits the growth of lung adenocarcinoma cancer cell xenografts in nude mice. This study has identified zinc pyrithione, an FDA-approved pharmacological agent with potential antitumor properties as a proteasomal DUB inhibitor.

Original languageEnglish (US)
Pages (from-to)13942-13956
Number of pages15
JournalOncotarget
Volume8
Issue number8
DOIs
StatePublished - Jan 1 2017

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Keywords

  • DNA damage
  • Deubiquitinases
  • Proteasome
  • Tumor
  • Zinc pyrithione

ASJC Scopus subject areas

  • Oncology

Cite this

Zhao, C., Chen, X., Yang, C., Zang, D., Lan, X., Liao, S., Zhang, P., Wu, J., Li, X., Liu, N., Liao, Y., Huang, H., Shi, X., Jiang, L., Liu, X., Ping Dou, Q., Wang, X., & Liu, J. (2017). Repurposing an antidandruff agent to treating cancer: Zinc pyrithione inhibits tumor growth via targeting proteasome-associated deubiquitinases. Oncotarget, 8(8), 13942-13956. https://doi.org/10.18632/oncotarget.14572