p62 as a therapeutic target for inhibition of autophagy in prostate cancer

Lei Wang, Donghern Kim, James T.F. Wise, Xianglin Shi, Zhuo Zhang, Robert S. DiPaola

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Background: To test the hypothesis that p62 is an optimal target for autophagy inhibition and Verteporfin, a clinically available drug approved by FDA to treat macular degeneration that inhibits autophagy by targeting p62 protein, can be developed clinically to improve therapy for advanced prostate cancer. Methods: Forced expression of p62 in PC-3 cells and normal prostate epithelial cells, RWPE-1 and PZ-HPV7, were carried out by transfection of these cells with pcDNA3.1/p62 or p62 shRNA plasmid. Autophagosomes and autophagic flux were measured by transfection of tandem fluorescence protein mCherry-GFP-LC3 construct. Apoptosis was measured by Annexin V/PI staining. Tumorigenesis was measured by a xenograft tumor growth model. Results: Verteporfin inhibited cell growth and colony formation in PC-3 cells. Verteporfin generated crosslinked p62 oligomers, resulting in inhibition of autophagy and constitutive activation of Nrf2 as well as its target genes, Bcl-2 and TNF-α. In normal prostate epithelial cells, forced expression of p62 caused constitutive Nrf2 activation, development of apoptosis resistance, and Verteporfin treatment exhibited inhibitory effects. Verteporfin treatment also inhibited starvation-induced autophagic flux of these cells. Verteporfin inhibited tumorigenesis of both normal prostate epithelial cells with p62 expression and prostate cancer cells and decreased p62, constitutive Nrf2, and Bcl-xL in xenograft tumor tissues, indicating that p62 can be developed as a drug target against prostate cancer. Conclusions: p62 has a high potential to be developed as a therapeutic target. Verteporfin represents a prototypical agent with therapeutic potential against prostate cancer through inhibition of autophagy by a novel mechanism of p62 inhibition.

Original languageEnglish
Pages (from-to)390-400
Number of pages11
JournalProstate
Volume78
Issue number5
DOIs
StatePublished - Apr 1 2018

Bibliographical note

Publisher Copyright:
© 2018 Wiley Periodicals, Inc.

Keywords

  • Nrf2
  • autophagy
  • p62
  • prostate cancer
  • verteporfin

ASJC Scopus subject areas

  • Oncology
  • Urology

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