Estefanía Moreno1, Clara Andradas2, Mireia Medrano1, María M. Caffarel2, Eduardo Pérez-Gómez2, Sandra Blasco-Benito2, María Gómez-Cañas2, M. Ruth Pazos2, Andrew J. Irving3, Carme Lluís1, Enric I. Canela1, Javier Fernández-Ruiz2, Manuel Guzmán2, Peter J. McCormick1 and Cristina Sánchez2*
+ Author Affiliations

1 University of Barcelona, Spain;
2 Complutense University, Spain;
3 University of Dundee, United Kingdom
↵* Corresponding author; email:

Background: Cannabinoid receptor CB2 and GPR55 are overexpressed in cancer cells and control cell fate.

Results: CB2R and GPR55 form heteromers in cancer cells which impact signaling of each protomer.

Conclusion: CB2R-GPR55 heteromers drive biphasic signaling responses as opposed to the individual receptors via cross-antagonism.

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Significance: These heteromers may explain some of the biphasic effects of cannabinoids and constitute potential new targets in oncology.


The G protein-coupled receptors CB2 (CB2R) and GPR55 are overexpressed in cancer cells and human tumors. As a modulation of GPR55 activity by cannabinoids has been suggested, we analyzed whether this receptor participates in cannabinoid effects on cancer cells. Here, we show that CB2R and GPR55 form heteromers in cancer cells, that these structures possess unique signaling properties, and that modulation of these heteromers can modify the antitumoral activity of cannabinoids in vivo. These findings unveil the existence of previously unknown signaling platforms that help explain the complex behavior of cannabinoids and may constitute new targets for therapeutic intervention in oncology.

cancer cannabinoid cannabinoid receptor G protein-coupled receptor (GPCR) signal transduction
Received March 4, 2014.
Accepted June 18, 2014.
Copyright © 2014, The American Society for Biochemistry and Molecular Biology