PIk1 inhibition enhances the efficacy of androgen signaling blockade in castration-resistant prostate cancer

Zhe Zhang, Xianzeng Hou, Chen Shao, Junjie Li, Ji Xin Cheng, Shihuan Kuang, Nihal Ahmad, Timothy Ratliff, Xiaoqi Liu

Research output: Contribution to journalArticlepeer-review

84 Scopus citations


Prostate cancer is thought to be driven by oxidative stress, lipid metabolism, androgen receptor (AR) signaling, and activation of the PI3K-AKT-mTOR pathway, but it is uncertain how they may become coordinated during progression to castration-resistant disease that remains incurable. The mitotic kinase polo-like kinase 1 (Plk1) is elevated in prostate cancer, where its expression is linked to tumor grade. Notably, Plk1 signaling and lipid metabolism were identified recently as two of the top five most upregulated pathways in a mouse xenograft model of human prostate cancer. Herein, we show that oxidative stress activates both the PI3K-AKT-mTOR pathway and AR signaling in a Plk1-dependent manner in prostate cells. Inhibition of the PI3K-AKT-mTOR pathway prevented oxidative stress-induced activation of AR signaling. Plk1 modulation also affected cholesteryl ester accumulation in prostate cancer via the SREBP pathway. Finally, Plk1 inhibition enhanced cellular responses to androgen signaling inhibitors (ASI) and overcame ASI resistance in both cultured prostate cancer cells and patient-derived tumor xenografts. Given that activation of AR signaling and the PI3K-AKT-mTOR pathway is sufficient to elevate SREBP-dependent expression of key lipid biosynthesis enzymes in castration-resistant prostate cancer (CRPC), our findings argued that Plk1 activation was responsible for coordinating and driving these processes to promote and sustain the development of this advanced stage of disease. Overall, our results offer a strong mechanistic rationale to evaluate Plk1 inhibitors in combination drug trials to enhance the efficacy of ASIs in CRPC.

Original languageEnglish
Pages (from-to)6635-6647
Number of pages13
JournalCancer Research
Issue number22
StatePublished - Nov 15 2014

Bibliographical note

Publisher Copyright:
© 2014 AACR.

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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