title: Glycogen synthase kinase-3β inhibition depletes the population of prostate cancer stem/progenitor-like cells and attenuates metastatic growth.
abstract: Cancer cells with stem or progenitor properties play a pivotal role in the initiation, recurrence and metastatic potential of solid tumors, including those of the human prostate. Cancer stem cells are generally more resistant to conventional therapies thus requiring the characterization of key pathways involved in the formation and/or maintenance of this malignant cellular subpopulation. To this end, we identified Glycogen Synthase Kinase-3β (GSK-3β) as a crucial kinase for the maintenance of prostate cancer stem/progenitor-like cells and pharmacologic inhibition of GSK-3β dramatically decreased the size of this cellular subpopulation. This was paralleled by impaired clonogenicity, decreased migratory potential and dramatic morphological changes. In line with our in vitro observations, treatment with a GSK-3β inhibitor leads to a complete loss of tumorigenicity and a decrease in metastatic potential in preclinical in vivo models. These observed anti-tumor effects appear to be largely Wnt-independent as simultaneous Wnt inhibition does not reverse the observed antitumor effects of GSK-3β blockage. We found that GSK-3β activity is linked to cytoskeletal protein F-actin and inhibition of GSK-3β leads to disturbance of F-actin polymerization. This may underlie the dramatic effects of GSK-3β inhibition on prostate cancer migration. Furthermore, GSK-3β inhibition led to strongly decreased expression of several integrin types including the cancer stem cell-associated α2β1 integrin. Taken together, our mechanistic observations highlight the importance of GSK-3β activity in prostate cancer stemness and may facilitate the development of novel therapy for advanced prostate cancer.
authors.affiliation: Department of Urology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Kroon
authors.affiliation: Department of Urology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Lars S
authors.initials: LS
authors.lastname: in 't Veld
authors.affiliation: Department of Urology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Jeroen T
authors.initials: JT
authors.lastname: Buijs
authors.affiliation: Department of Urology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Henry
authors.initials: H
authors.lastname: Cheung
authors.affiliation: Department of Urology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Geertje
authors.initials: G
authors.lastname: van der Horst
authors.affiliation: Department of Urology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Gabri
authors.initials: G
authors.lastname: van der Pluijm
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D038982:Integrin alpha2beta1 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000166:cytology*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D055503:Protein Multimerization / Q000187:drug effects; D051153:Wnt Proteins / Q000037:antagonists & inhibitors; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: D000199:Actins; D038982:Integrin alpha2beta1; D047428:Protein Kinase Inhibitors; D051153:Wnt Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3