Modulation of breast cancer cell viability by a cannabinoid receptor 2

We show that JWH-015 inhibits tumor cell viability and induces apoptosis of breast cancer cell lines (murine) 4T1 and (human) MCF7 in vitro and attenuates primary tumor growth and metastasis in vivo. Cells cultured in Ca2+-free media for 16 hours prior to treatment with JWH-015 experienced a significant dose–response curve shift (A50=9.80 μM; 95% CI =7.57–12.69) (Figure 6D). Treatment with either cannabidiol or O-1602 (concentrations from 0.1 to 10 μM) alone had no effect on cell viability. Two distinct cannabinoid receptors have been cloned: CB1,36 which is one of the most abundantly expressed G-protein-coupled receptors on neurons, and CB2,37 found primarily in cells of the immune system and on bone maintenance cells.14 In physiologically normal systems, CB1 and CB2 were first reported to couple predominantly with Gαi,38 yet several recent studies have demonstrated CB2 receptor signaling via Gαq and other alternative coupling pathways.39,40 Several groups have shown that both nonselective cannabinoid and CB2-specific compounds decrease breast cancer viability in vitro and in vivo: Δ9-tetrahydrocannabinol and CB2-selective agonist, JWH-133, have been demonstrated to exert considerable antitumoral effects in the MMTV-neu mouse model of breast cancer, which overexpresses the EGF receptor HER2.17 Similarly, CB2-selective JWH-133 has been shown to retard growth and metastasis of aggressive spontaneous breast tumors occurring in PyMT transgenic mice, implying the cyclooxygenase-2/prostaglandin E2 signaling pathway.34 Cannabidiol inhibited human breast cancer cell line MDA-MB-231 growth in vitro by inducing apoptosis and autophagy.8 Anandamide, an endogenous cannabinoid CB1 agonist, has been shown to inhibit breast cancer cell growth and migration in multiple models,41,42 and several other studies have demonstrated CB2 agonist efficacy in breast cancer systems;43–45 however, the mechanism(s) of how cannabinoids achieve these effects is incompletely defined. Consistent with the findings on the intracellular activity of cannabinoids by other groups,7,22,57–59 we have demonstrated that CB2-selective JWH-015 reduces phosphorylation of ERK1/2 at time points relevant to peak measured caspase 3/7 activity, suggesting that the apoptosis induced by JWH-015 in breast cancer cells may be mediated by MAPK/ERK activity.

Visit Link