ZFIN ID: ZDB-PUB-140513-190
Glycogen synthase kinase 3 inhibitors induce the canonical WNT/β-catenin pathway to suppress growth and self-renewal in embryonal rhabdomyosarcoma
Chen, E.Y., Deran, M.T., Ignatius, M.S., Grandinetti, K.B., Clagg, R., McCarthy, K.M., Lobbardi, R.M., Brockmann, J., Keller, C., Wu, X., Langenau, D.M.
Date: 2014
Source: Proc. Natl. Acad. Sci. USA 111(14): 5349-54 (Journal)
Registered Authors: Ignatius, Myron, Langenau, David
Keywords: none
MeSH Terms:
  • Animals
  • Cell Line
  • Enzyme Inhibitors/pharmacology*
  • Glycogen Synthase Kinase 3/antagonists & inhibitors*
  • Humans
  • Rhabdomyosarcoma, Embryonal/enzymology
  • Rhabdomyosarcoma, Embryonal/metabolism
  • Rhabdomyosarcoma, Embryonal/pathology*
  • Wnt Signaling Pathway/drug effects*
  • Zebrafish
  • beta Catenin/metabolism*
PubMed: 24706870 Full text @ Proc. Natl. Acad. Sci. USA
FIGURES
ABSTRACT
Embryonal rhabdomyosarcoma (ERMS) is a common pediatric malignancy of muscle, with relapse being the major clinical challenge. Self-renewing tumor-propagating cells (TPCs) drive cancer relapse and are confined to a molecularly definable subset of ERMS cells. To identify drugs that suppress ERMS self-renewal and induce differentiation of TPCs, a large-scale chemical screen was completed. Glycogen synthase kinase 3 (GSK3) inhibitors were identified as potent suppressors of ERMS growth through inhibiting proliferation and inducing terminal differentiation of TPCs into myosin-expressing cells. In support of GSK3 inhibitors functioning through activation of the canonical WNT/:beta;-catenin pathway, recombinant WNT3A and stabilized β-catenin also enhanced terminal differentiation of human ERMS cells. Treatment of ERMS-bearing zebrafish with GSK3 inhibitors activated the WNT/β-catenin pathway, resulting in suppressed ERMS growth, depleted TPCs, and diminished self-renewal capacity in vivo. Activation of the canonical WNT/β-catenin pathway also significantly reduced self-renewal of human ERMS, indicating a conserved function for this pathway in modulating ERMS self-renewal. In total, we have identified an unconventional tumor suppressive role for the canonical WNT/β-catenin pathway in regulating self-renewal of ERMS and revealed therapeutic strategies to target differentiation of TPCs in ERMS.
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