Plk1 inhibition enhances the efficacy of androgen signaling blockade in castration-resistant prostate cancer.

Abstract

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.

• Authors: Zhe Zhang, Xianzeng Hou, Chen Shao, Junjie Li, Ji-Xin Cheng, Shihuan Kuang, Nihal Ahmad, Timothy Ratliff, Xiaoqi Liu
• Journal: Cancer research (Cancer Res) Vol. 74 Issue 22 Pg. 6635-47 (Nov 15 2014) ISSN: 1538-7445 [Electronic] United States
• PMID: 25252916 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Androgen Antagonists
• Cell Cycle Proteins
• NF-kappa B
• Proto-Oncogene Proteins
• SREBF1 protein, human
• Sterol Regulatory Element Binding Protein 1
• Cholesterol
• MTOR protein, human
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases

Topics

• Androgen Antagonists (therapeutic use)
• Cell Cycle Proteins (antagonists & inhibitors)
• Cell Line, Tumor
• Cholesterol (metabolism)
• Drug Resistance, Neoplasm
• Humans
• Male
• NF-kappa B (physiology)
• Oxidative Stress
• Phosphatidylinositol 3-Kinases (physiology)
• Prostatic Neoplasms, Castration-Resistant (drug therapy, metabolism)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Proto-Oncogene Proteins (antagonists & inhibitors)
• Proto-Oncogene Proteins c-akt (physiology)
• Signal Transduction (drug effects)
• Sterol Regulatory Element Binding Protein 1 (physiology)
• TOR Serine-Threonine Kinases (physiology)
• Polo-Like Kinase 1