Abstract
Alveolar rhabdomyosarcoma (ARMS) is a muscle-derived childhood tumor characterized by production of oncogenic PAX3/7-FOXO1 chimeric transcription factors. While downstream targets of the PAX3-FOXO1 oncoprotein in ARMS have been defined, the functional relevance of these targets is unclear. Here, we show that upregulation of the cannabinoid receptor 1 (Cnr1/Cb1) by PAX3-FOXO1 in mouse primary myoblasts and ARMS cell lines, contributes to PAX3-FOXO1 phenotypes, both in vivo and in vitro. In primary myoblasts, Cnr1 was dispensable for PAX3-FOXO1 to mediate cell proliferation, differentiation, or transformation; however, Cnr1 function was essential to increase the invasive capacity conferred by PAX3-FOXO1 overexpression in these cells. Genetic or pharmacologic abrogation of Cnr1 inhibited the enhanced basement membrane invasion induced by PAX3-FOXO1. Cnr1 loss by either route also dramatically reduced lung metastasis formation. Taken together, our findings strongly implicate Cnr1 as a novel tractable target to inhibit ARMS invasion and metastasis.
Publication types
- Research Support, Non-U.S. Gov't
MeSH terms
- Animals
- Blotting, Western
- Cell Line, Tumor
- Cell Movement*
- Cell Transformation, Neoplastic / drug effects
- Cells, Cultured
- Cyclin-Dependent Kinase Inhibitor p16 / genetics
- Cyclin-Dependent Kinase Inhibitor p16 / metabolism
- Humans
- Lung Neoplasms / genetics
- Lung Neoplasms / metabolism
- Lung Neoplasms / secondary
- Mice
- Mice, Inbred C57BL
- Mice, Inbred NOD
- Mice, Knockout
- Mice, SCID
- Myoblasts / cytology
- Myoblasts / drug effects
- Myoblasts / metabolism
- Neoplasm Invasiveness
- Neoplasm Metastasis
- Neoplasms, Experimental / genetics
- Neoplasms, Experimental / metabolism
- Neoplasms, Experimental / pathology
- Oncogene Proteins, Fusion / genetics
- Oncogene Proteins, Fusion / metabolism*
- Paired Box Transcription Factors / genetics
- Paired Box Transcription Factors / metabolism*
- Piperidines / pharmacology
- Pyrazoles / pharmacology
- Receptor, Cannabinoid, CB1 / antagonists & inhibitors
- Receptor, Cannabinoid, CB1 / genetics
- Receptor, Cannabinoid, CB1 / metabolism*
- Reverse Transcriptase Polymerase Chain Reaction
- Rhabdomyosarcoma, Alveolar / genetics
- Rhabdomyosarcoma, Alveolar / metabolism
- Rhabdomyosarcoma, Alveolar / pathology
- Tumor Suppressor Protein p14ARF / genetics
- Tumor Suppressor Protein p14ARF / metabolism
Substances
- Cyclin-Dependent Kinase Inhibitor p16
- Oncogene Proteins, Fusion
- PAX3-FOXO1A fusion protein, human
- Paired Box Transcription Factors
- Piperidines
- Pyrazoles
- Receptor, Cannabinoid, CB1
- Tumor Suppressor Protein p14ARF
- AM 251