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.
Publication types
- Research Support, Non-U.S. Gov't
MeSH terms
- Animals
- Apoptosis / drug effects*
- Basic Helix-Loop-Helix Transcription Factors / genetics
- Basic Helix-Loop-Helix Transcription Factors / metabolism
- Blotting, Western
- Cell Proliferation / drug effects
- Dronabinol / analogs & derivatives*
- Dronabinol / pharmacology*
- Female
- Glycogen Synthase Kinase 3 / genetics
- Glycogen Synthase Kinase 3 / metabolism
- Glycogen Synthase Kinase 3 beta
- Humans
- Immunoenzyme Techniques
- Mice
- Mice, Inbred NOD
- Mice, SCID
- Neoplasm Proteins / genetics
- Neoplasm Proteins / metabolism
- Oncogene Proteins, Fusion / genetics
- PAX7 Transcription Factor / genetics
- Proto-Oncogene Proteins c-akt / genetics
- Proto-Oncogene Proteins c-akt / metabolism
- RNA, Messenger / genetics
- RNA, Messenger / metabolism
- Receptor, Cannabinoid, CB1 / antagonists & inhibitors*
- Receptor, Cannabinoid, CB1 / genetics
- Receptor, Cannabinoid, CB1 / metabolism
- Receptors, Interleukin-2 / physiology
- Reverse Transcriptase Polymerase Chain Reaction
- Rhabdomyosarcoma / genetics
- Rhabdomyosarcoma / metabolism
- Rhabdomyosarcoma / pathology*
- Translocation, Genetic*
- Tumor Cells, Cultured
- Xenograft Model Antitumor Assays
Substances
- 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