jwh-133 and Colonic-Neoplasms

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.

Topics: Animals; Antigens, CD; Apoptosis; Cadherins; Cannabinoids; Cell Line, Tumor; Cell Membrane; Cell Proliferation; Cell Survival; Colonic Neoplasms; Disease Progression; Enzyme Activation; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Glycogen Synthase Kinase 3 beta; HT29 Cells; Humans; Mice; Mice, Nude; Microscopy, Confocal; Neoplasm Transplantation; Proto-Oncogene Proteins c-akt; Receptor, Cannabinoid, CB2; Signal Transduction

Cell migration is of paramount importance in physiological processes such as immune surveillance, but also in the pathological processes of tumor cell migration and metastasis development. The factors that regulate this tumor cell migration, most prominently neurotransmitters, have thus been the focus of intense investigation. While the majority of neurotransmitters have a stimulatory effect on cell migration, we herein report the inhibitory effect of the endogenous substance anandamide on both tumor cell and lymphocyte migration. Using a collagen-based three-dimensional migration assay and time-lapse videomicroscopy, we have observed that the anandamide-mediated signals for CD8+ T lymphocytes and SW 480 colon carcinoma cells are each mediated by distinct cannabinoid receptors (CB-Rs). Using the specific agonist docosatetraenoylethanolamide (DEA), we have observed that the norepinephrine-induced migration of colon carcinoma cells is inhibited by the CB1-R. The SDF-1-induced migration of CD8+ T lymphocytes was, however, inhibited via the CB2-R, as shown by using the specific agonist JWH 133. Therefore, specific inhibition of tumor cell migration via CB1-R engagement might be a selective tool to prevent metastasis formation without depreciatory effects on the immune system of cancer patients.

Topics: Adrenergic alpha-Agonists; Arachidonic Acids; Calcium Channel Blockers; Cannabinoids; Cell Movement; Collagen; Colonic Neoplasms; Endocannabinoids; Humans; Norepinephrine; Polyunsaturated Alkamides; Receptors, Cannabinoid; T-Lymphocytes; Tumor Cells, Cultured