title: Cotargeting Polo-Like Kinase 1 and the Wnt/β-Catenin Signaling Pathway in Castration-Resistant Prostate Cancer.
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.
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Biological Science, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Anju
authors.initials: A
authors.lastname: Karki
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Kurt B
authors.initials: KB
authors.lastname: Hodges
authors.affiliation: Department of Dermatology, University of Wisconsin, Madison, Madison, Wisconsin, USA.
authors.forename: Nihal
authors.initials: N
authors.lastname: Ahmad
authors.affiliation: The Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
authors.forename: Amina
authors.initials: A
authors.lastname: Zoubeidi
authors.affiliation: Department of Obstetrics and Gynecology, J. W. Goethe University, Frankfurt, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Strebhardt
authors.affiliation: Center for Cancer Research, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Ratliff
authors.affiliation: Department of Biological Science, Purdue University, West Lafayette, Indiana, USA Center for Cancer Research, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Konieczny
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana, USA Center for Cancer Research, Purdue University, West Lafayette, Indiana, USA liu8@purdue.edu.
authors.forename: Xiaoqi
authors.initials: X
authors.lastname: Liu
mesh_terms: D000818:Animals; D050256:Antimitotic Agents / Q000494:pharmacology; D060466:Axin Protein / Q000378:metabolism; D064199:Cdc20 Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011621:Pteridines / Q000494:pharmacology; D014183:Transplantation, Heterologous; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000097869:Polo-Like Kinase 1
chemical_list: D050256:Antimitotic Agents; D060466:Axin Protein; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D051153:Wnt Proteins; D051176:beta Catenin; D000097869:Polo-Like Kinase 1; C491761:AXIN2 protein, human; C518477:BI 2536; C577488:CDC20 protein, human; C000605506:GSK3B protein, human; C000605507:Gsk3b protein, mouse