CXCR4 Promotes Neuroblastoma Growth and Therapeutic Resistance through miR-15a/16-1-Mediated ERK and BCL2/Cyclin D1 Pathways.

Abstract

CXCR4 expression in neuroblastoma tumors correlates with disease severity. In this study, we describe mechanisms by which CXCR4 signaling controls neuroblastoma tumor growth and response to therapy. We found that overexpression of CXCR4 or stimulation with CXCL12 supports neuroblastoma tumorigenesis. Moreover, CXCR4 inhibition with the high-affinity CXCR4 antagonist BL-8040 prevented tumor growth and reduced survival of tumor cells. These effects were mediated by the upregulation of miR-15a/16-1, which resulted in downregulation of their target genes BCL-2 and cyclin D1, as well as inhibition of ERK. Overexpression of miR-15a/16-1 in cells increased cell death, whereas antagomirs to miR-15a/16-1 abolished the proapoptotic effects of BL-8040. CXCR4 overexpression also increased miR-15a/16-1, shifting their oncogenic dependency from the BCL-2 to the ERK signaling pathway. Overall, our results demonstrate the therapeutic potential of CXCR4 inhibition in neuroblastoma treatment and provide a rationale to test combination therapies employing CXCR4 and BCL-2 inhibitors to increase the efficacy of these agents.Significance: These results provide a mechanistic rationale for combination therapy of CXCR4 and BCL-2 inhibitors to treat a common and commonly aggressive pediatric cancer.Cancer Res; 78(6); 1471-83. ©2017 AACR.

• Authors: Shiri Klein, Michal Abraham, Baruch Bulvik, Elia Dery, Ido D Weiss, Neta Barashi, Rinat Abramovitch, Hanna Wald, Yaniv Harel, Devorah Olam, Lola Weiss, Katia Beider, Orly Eizenberg, Ori Wald, Eithan Galun, Yaron Pereg, Amnon Peled
• Journal: Cancer research (Cancer Res) Vol. 78 Issue 6 Pg. 1471-1483 (03 15 2018) ISSN: 1538-7445 [Electronic] United States
• PMID: 29259008 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• 4-fluorobenzoyl-TN-14003
• BCL2 protein, human
• CCND1 protein, human
• CXCR4 protein, human
• MIRN15 microRNA, human
• MIRN16 microRNA, human
• MicroRNAs
• Peptides
• Proto-Oncogene Proteins c-bcl-2
• Receptors, CXCR4
• Cyclin D1

Topics

• Animals
• Brain Neoplasms (drug therapy, genetics, pathology)
• Cell Line, Tumor
• Cyclin D1 (genetics, metabolism)
• Drug Resistance, Neoplasm (drug effects, genetics)
• Gene Expression Regulation, Neoplastic
• Humans
• MAP Kinase Signaling System (drug effects, genetics)
• Mice
• MicroRNAs (genetics, metabolism)
• Neuroblastoma (drug therapy, genetics, pathology)
• Peptides (pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• Receptors, CXCR4 (antagonists & inhibitors, genetics, metabolism)
• Xenograft Model Antitumor Assays