Glycogen synthase kinase 3 inhibitors induce the canonical WNT/β-catenin pathway to suppress growth and self-renewal in embryonal rhabdomyosarcoma

• Published in: Proceedings of the National Academy of Sciences - PNAS 2014-04, Vol.111 (14), p.5349-5354
• Main Authors: Chen, Eleanor Y., DeRan, Michael T., Ignatius, Myron S., Grandinetti, Kathryn Brooke, Clagg, Ryan, McCarthy, Karin M., Lobbardi, Riadh M., Brockmann, Jillian, Keller, Charles, Wu, Xu, Langenau, David M.
• Format: Article
• Language: English
• Subjects: Animals; beta Catenin - metabolism; Biological Sciences; Cancer; Cell growth; Cell Line; Cell lines; Cellular differentiation; Danio rerio; Embryonic stem cells; Enzyme Inhibitors - pharmacology; Glycogen Synthase Kinase 3 - antagonists & inhibitors; Human growth; Humans; Rhabdomyosarcoma; Rhabdomyosarcoma, Embryonal - enzymology; Rhabdomyosarcoma, Embryonal - metabolism; Rhabdomyosarcoma, Embryonal - pathology; Stem cells; Tumor cell line; Tumors; Wnt Signaling Pathway - drug effects; Zebrafish
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1317731111

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/β-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.