title: CB2 cannabinoid receptor activation promotes colon cancer progression via AKT/GSK3β signaling pathway.
abstract: 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 cancer.
authors.affiliation: Department of Medical Oncology, Hospital Universitario Puerta de Hierro-Majadahonda, E-28222 Madrid, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Martínez-Martínez
authors.affiliation: Department of Medical Oncology, Hospital Universitario Puerta de Hierro-Majadahonda, E-28222 Madrid, Spain.
authors.forename: Asunción
authors.initials: A
authors.lastname: Martín-Ruiz
authors.affiliation: Department of Pathology, Hospital Universitario Puerta de Hierro-Majadahonda, E-28222 Madrid, Spain.
authors.forename: Paloma
authors.initials: P
authors.lastname: Martín
authors.affiliation: Department of Medical Oncology, Hospital Universitario Puerta de Hierro-Majadahonda, E-28222 Madrid, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Calvo
authors.affiliation: Department of Medical Oncology, Hospital Universitario Puerta de Hierro-Majadahonda, E-28222 Madrid, Spain.
authors.forename: Mariano
authors.initials: M
authors.lastname: Provencio
authors.affiliation: Department of Medical Oncology, Hospital Universitario Puerta de Hierro-Majadahonda, E-28222 Madrid, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: García
mesh_terms: D000818:Animals; D015703:Antigens, CD; D017209:Apoptosis; D015820:Cadherins / Q000378:metabolism; D002186:Cannabinoids / Q000737:chemistry; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D018450:Disease Progression; D004789:Enzyme Activation; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D009368:Neoplasm Transplantation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; C588309:CNR2 protein, human; D015820:Cadherins; D002186:Cannabinoids; D043885:Receptor, Cannabinoid, CB2; C402416:HU 308; C494918:AKT1 protein, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC
keywords: AKT/PKB; CB2; JWH-133; colon cancer; proliferation