title: Modulation of breast cancer cell viability by a cannabinoid receptor 2 agonist, JWH-015, is calcium dependent.
abstract: BACKGROUND
  Cannabinoid compounds, both nonspecific as well as agonists selective for either cannabinoid receptor 1 (CB1) or cannabinoid receptor 2 (CB2), have been shown to modulate the tumor microenvironment by inducing apoptosis in tumor cells in several model systems. The mechanism of this modulation remains only partially delineated, and activity induced via the CB1 and CB2 receptors may be distinct despite significant sequence homology and structural similarity of ligands.
  
  
  METHODS
  The CB2-selective agonist JWH-015 was used to investigate mechanisms downstream of CB2 activation in mouse and human breast cancer cell lines in vitro and in a murine mammary tumor model.
  
  
  RESULTS
  JWH-015 treatment significantly reduced primary tumor burden and metastasis of luciferase-tagged murine mammary carcinoma 4T1 cells in immunocompetent mice in vivo. Furthermore, JWH-015 reduced the viability of murine 4T1 and human MCF7 mammary carcinoma cells in vitro by inducing apoptosis. JWH-015-mediated reduction of breast cancer cell viability was not dependent on Gαi signaling in vitro or modified by classical pharmacological blockade of CB1, GPR55, TRPV1, or TRPA1 receptors. JWH-015 effects were calcium dependent and induced changes in MAPK/ERK signaling.
  
  
  CONCLUSIONS
  The results of this work characterize the actions of a CB2-selective agonist on breast cancer cells in a syngeneic murine model representing how a clinical presentation of cancer progression and metastasis may be significantly modulated by a G-protein-coupled receptor.
authors.affiliation: Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA; Department of Biomedical Sciences, University of New England College of Osteopathic Medicine, Biddeford, ME, USA.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Hanlon
authors.affiliation: Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA.
authors.forename: Alysia N
authors.initials: AN
authors.lastname: Lozano-Ondoua
authors.affiliation: Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA.
authors.forename: Puja J
authors.initials: PJ
authors.lastname: Umaretiya
authors.affiliation: Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Symons-Liguori
authors.affiliation: Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA.
authors.forename: Anupama
authors.initials: A
authors.lastname: Chandramouli
authors.affiliation: Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA.
authors.forename: Jamie K
authors.initials: JK
authors.lastname: Moy
authors.affiliation: Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA.
authors.forename: William K
authors.initials: WK
authors.lastname: Kwass
authors.affiliation: Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA.
authors.forename: Patrick W
authors.initials: PW
authors.lastname: Mantyh
authors.affiliation: Department of Pathology, University of Arizona College of Medicine, Tucson, AZ, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Nelson
authors.affiliation: Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA.
authors.forename: Todd W
authors.initials: TW
authors.lastname: Vanderah
keywords: CB2; JWH-015; MAPK/ERK; apoptosis; breast cancer; calcium; cannabinoid receptor-2