Cannabinoid receptor 1 is a potential drug target for treatment of translocation-positive rhabdomyosarcoma.

Abstract

Gene expression profiling has revealed that the gene coding for cannabinoid receptor 1 (CB1) is highly up-regulated in rhabdomyosarcoma biopsies bearing the typical chromosomal translocations PAX3/FKHR or PAX7/FKHR. Because cannabinoid receptor agonists are capable of reducing proliferation and inducing apoptosis in diverse cancer cells such as glioma, breast cancer, and melanoma, we evaluated whether CB1 is a potential drug target in rhabdomyosarcoma. Our study shows that treatment with the cannabinoid receptor agonists HU210 and Delta(9)-tetrahydrocannabinol lowers the viability of translocation-positive rhabdomyosarcoma cells through the induction of apoptosis. This effect relies on inhibition of AKT signaling and induction of the stress-associated transcription factor p8 because small interfering RNA-mediated down-regulation of p8 rescued cell viability upon cannabinoid treatment. Finally, treatment of xenografts with HU210 led to a significant suppression of tumor growth in vivo. These results support the notion that cannabinoid receptor agonists could represent a novel targeted approach for treatment of translocation-positive rhabdomyosarcoma.

• Authors: Susanne Oesch, Dagmar Walter, Marco Wachtel, Kathya Pretre, Maria Salazar, Manuel Guzmán, Guillermo Velasco, Beat W Schäfer
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 8 Issue 7 Pg. 1838-45 (Jul 2009) ISSN: 1538-8514 [Electronic] United States
• PMID: 19509271 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• NUPR1 protein, human
• Neoplasm Proteins
• Oncogene Proteins, Fusion
• PAX3-FKHR fusion protein, human
• PAX7 Transcription Factor
• PAX7 protein, human
• RNA, Messenger
• Receptor, Cannabinoid, CB1
• Receptors, Interleukin-2
• Dronabinol
• Glycogen Synthase Kinase 3 beta
• Proto-Oncogene Proteins c-akt
• Glycogen Synthase Kinase 3
• HU 211

Topics

• Animals
• Apoptosis (drug effects)
• Basic Helix-Loop-Helix Transcription Factors (genetics, metabolism)
• Blotting, Western
• Cell Proliferation (drug effects)
• Dronabinol (analogs & derivatives, pharmacology)
• Female
• Glycogen Synthase Kinase 3 (genetics, metabolism)
• Glycogen Synthase Kinase 3 beta
• Humans
• Immunoenzyme Techniques
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Neoplasm Proteins (genetics, metabolism)
• Oncogene Proteins, Fusion (genetics)
• PAX7 Transcription Factor (genetics)
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• RNA, Messenger (genetics, metabolism)
• Receptor, Cannabinoid, CB1 (antagonists & inhibitors, genetics, metabolism)
• Receptors, Interleukin-2 (physiology)
• Reverse Transcriptase Polymerase Chain Reaction
• Rhabdomyosarcoma (genetics, metabolism, pathology)
• Translocation, Genetic
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays