Cannabinoid receptor 1 is a potential drug target for treatment of translocation-positive rhabdomyosarcoma.
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.
Oesch
Susanne
S
Department of Oncology, University Children's Hospital, Zurich, Switzerland.
Walter
Dagmar
D
Wachtel
Marco
M
Pretre
Kathya
K
Salazar
Maria
M
Guzmán
Manuel
M
Velasco
Guillermo
G
Schäfer
Beat W
BW
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D051763:PAX7 Transcription Factor / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012208:Rhabdomyosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D051792:Basic Helix-Loop-Helix Proteins; D013759:Dronabinol; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D051763:PAX7 Transcription Factor; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D015375:Receptors, Interleukin-2; C491643:NUPR1 protein, human; C523321:PAX3-FKHR fusion protein, human; C497321:PAX7 protein, human; C062018:HU 211