The pharmacological activation of the cannabinoid receptor type 2, CB2, has been
shown to elicit anti-tumoral mechanisms in different cancer types. However, little is
known about its endogenous role in tumor pathophysiology, and different studies
have attributed pro-tumorigenic properties to this receptor. In a previous work, we
showed that CB2 expression is a poor prognostic factor in colon cancer patients.
Here we report that activation of CB2 with low doses of specific agonists induce cell
proliferation and favor the acquisition of aggressive molecular features in colon cancer
cells. We show that sub-micromolar concentrations of CB2-specific agonists, JWH-133
and HU-308, promote an increase in cell proliferation rate through the activation of
AKT/PKB pathway in colon cancer in vitro and in vivo. AKT activation promotes GSK3β
inhibition and thus, a more aggressive cell phenotype with the subsequent elevation
of SNAIL levels, E-cadherin degradation and β-catenin delocalization from cell
membrane. Taken together, our data show that CB2 activation with sub-micromolar
doses of agonists, which could be more similar to endogenous levels of cannabinoids,
promote colon cancer progression, implicating that CB2 could have a pro-tumorigenic
endogenous role in colon cancerThis work was supported by grants from Fondo de Investigaciones Sanitarias (ISCIII-PI10/00879 to JMG; Plan Nacional de I+D+I 2008-2011, FEDER funds co-financed), Red Temática de Investigación Cooperativa en Cáncer (ISCIII-RETIC RD12/0036/0041; Plan Estatal de I+D+I 2013-2016, FEDER funds cofinanced). JMG and PM were supported by ISCIII CP08/00217 and JR14/0018 contracts, respectively. EMM was recipient of ISCIII PFIS PhD studentship (FI11/00696) (Plan Nacional de I+D+I 2008-2011, FEDER funds co-financed); AMR was recipient of PhD contract from Department of Medical Oncology of H.U. Puerta de Hierro; VC was recipient of attending physician contract in Medical Oncology Department from H.U. Puerta de Hierro; MP was supported by Universidad Autónoma de Madrid (UAM) with Full Professor contrac
