title: 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.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana. State Key Laboratory for Agrobiotechnology and Department of Microbiology, China Agricultural University, Beijing, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana. Department of Neurosurgery, Qianfoshan Hospital affiliated to Shandong University, Jinan, China.
authors.forename: Xianzeng
authors.initials: X
authors.lastname: Hou
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana.
authors.forename: Chen
authors.initials: C
authors.lastname: Shao
authors.affiliation: Department of Biomedical Engineering, Purdue University, West Lafayette, Indiana.
authors.forename: Junjie
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Biomedical Engineering, Purdue University, West Lafayette, Indiana.
authors.forename: Ji-Xin
authors.initials: JX
authors.lastname: Cheng
authors.affiliation: Department of Animal Sciences, Purdue University, West Lafayette, Indiana.
authors.forename: Shihuan
authors.initials: S
authors.lastname: Kuang
authors.affiliation: Department of Dermatology, University of Wisconsin, Madison, Wisconsin.
authors.forename: Nihal
authors.initials: N
authors.lastname: Ahmad
authors.affiliation: Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana.
authors.forename: Timothy
authors.initials: T
authors.lastname: Ratliff
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana. Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana. liu8@purdue.edu.
authors.forename: Xiaoqi
authors.initials: X
authors.lastname: Liu
mesh_terms: D000726:Androgen Antagonists / Q000627:therapeutic use*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D016328:NF-kappa B / Q000502:physiology; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D051780:Sterol Regulatory Element Binding Protein 1 / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000502:physiology; D000097869:Polo-Like Kinase 1
chemical_list: D000726:Androgen Antagonists; D018797:Cell Cycle Proteins; D002784:Cholesterol; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D051780:Sterol Regulatory Element Binding Protein 1; D058570:TOR Serine-Threonine Kinases; D000097869:Polo-Like Kinase 1; C497387:SREBF1 protein, human; C546842:MTOR protein, human