Rho-associated kinase is a therapeutic target in neuroblastoma.

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 3β-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.

• Authors: Cecilia Dyberg, Susanne Fransson, Teodora Andonova, Baldur Sveinbjörnsson, Jessika Lännerholm-Palm, Thale K Olsen, David Forsberg, Eric Herlenius, Tommy Martinsson, Bertha Brodin, Per Kogner, John Inge Johnsen, Malin Wickström
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 114 Issue 32 Pg. E6603-E6612 (08 08 2017) ISSN: 1091-6490 [Electronic] United States
• PMID: 28739902 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• MYCN protein, human
• N-Myc Proto-Oncogene Protein
• Protein Kinase Inhibitors
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• ROCK1 protein, human
• ROCK2 protein, human
• rho-Associated Kinases

Topics

• Animals
• Cell Line, Tumor
• Glycogen Synthase Kinase 3 beta (metabolism)
• Humans
• Mice
• Mice, Nude
• N-Myc Proto-Oncogene Protein (metabolism)
• Neuroblastoma (drug therapy, enzymology, pathology)
• Protein Kinase Inhibitors
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays
• rho-Associated Kinases (antagonists & inhibitors, metabolism)