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Rho-associated kinase is a therapeutic target in neuroblastoma

Journal article
Authors C. Dyberg
Susanne Fransson
T. Andonova
B. Sveinbjornsson
J. Lannerholm-Palm
T. K. Olsen
D. Forsberg
E. Herlenius
Tommy Martinsson
B. Brodin
P. Kogner
J. I. Johnsen
M. Wickstrom
Published in Proceedings of the National Academy of Sciences of the United States of America
Volume 114
Issue 32
Pages E6603-E6612
ISSN 0027-8424
Publication year 2017
Published at Institute of Biomedicine, Department of Medical and Clinical Genetics
Pages E6603-E6612
Language en
Links doi.org/10.1073/pnas.1706011114
Keywords neuroblastoma, Rho signaling, ROCK, personalized medicine, Wnt signaling, HIGH-RISK NEUROBLASTOMA, CELL-MIGRATION, NERVOUS-SYSTEM, MUTATIONS, PROTEIN, INHIBITION, MELANOMA, DEATH
Subject categories Cancer and Oncology

Abstract

Neuroblastoma is a peripheral neural system tumor that originates from the neural crest and is the most common and deadly tumor of infancy. Here we show that neuroblastoma harbors frequent mutations of genes controlling the Rac/Rho signaling cascade important for proper migration and differentiation of neural crest cells during neuritogenesis. RhoA is activated in tumors from neuroblastoma patients, and elevated expression of Rho-associated kinase (ROCK) 2 is associated with poor patient survival. Pharmacological or genetic inhibition of ROCK1 and 2, key molecules in Rho signaling, resulted in neuroblastoma cell differentiation and inhibition of neuroblastoma cell growth, migration, and invasion. Molecularly, ROCK inhibition induced glycogen synthase kinase 3 beta-dependent phosphorylation and degradation of MYCN protein. Small-molecule inhibition of ROCK suppressed MYCN-driven neuroblastoma growth in TH-MYCN homozygous transgenic mice and MYCN gene-amplified neuroblastoma xenograft growth in nude mice. Interference with Rho/Rac signaling might offer therapeutic perspectives for high-risk neuroblastoma.

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