Cotargeting polo-like kinase 1 and the Wnt/β-catenin signaling pathway in castration-resistant prostate cancer

Jie Li, Anju Karki, Kurt B. Hodges, Nihal Ahmad, Amina Zoubeidi, Klaus Strebhardt, Timothy L. Ratliff, Stephen F. Konieczny, Xiaoqi Liu

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

The Wnt/β-catenin signaling pathway has been identified as one of the predominantly upregulated pathways in castration-resistant prostate cancer (CRPC). However, whether targeting the β-catenin pathway will prove effective as a CRPC treatment remains unknown. Polo-like kinase 1 (Plk1) is a critical regulator in many cell cycle events, and its level is significantly elevated upon castration of mice carrying xenograft prostate tumors. Indeed, inhibition of Plk1 has been shown to inhibit tumor growth in several in vivo studies. Here, we show that Plk1 is a negative regulator of Wnt/β-catenin signaling. Plk1 inhibition or depletion enhances the level of cytosolic and nuclear β-catenin in human prostate cancer cells. Furthermore, inhibition of Wnt/β- catenin signaling significantly potentiates the antineoplastic activity of the Plk1 inhibitor BI2536 in both cultured prostate cancer cells and CRPC xenograft tumors. Mechanistically, axin2, a negative regulator of the β-catenin pathway, serves as a substrate of Plk1, and Plk1 phosphorylation of axin2 facilitates the degradation of β-catenin by enhancing binding between glycogen synthase kinase 3β (GSK3β) and β-catenin. Plk1-phosphorylated axin2 also exhibits resistance to Cdc20-mediated degradation. Overall, this study identifies a novel Plk1-Wnt signaling axis in prostate cancer, offering a promising new therapeutic option to treat CRPC.

Original languageEnglish
Pages (from-to)4185-4198
Number of pages14
JournalMolecular and Cellular Biology
Volume35
Issue number24
DOIs
StatePublished - 2015

Bibliographical note

Publisher Copyright:
© 2015, American Society for Microbiology.

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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