Cannabinoid Receptor Type 2 Agonist, GW405833, Reduced the Impacts of MDA‐MB‐231 Breast Cancer Cells on Bone Cells

Abstract

ABSTRACT Aim Breast cancer frequently metastasizes to bones. The interaction between breast cancer cells and bone cells results in osteolytic lesions by disrupting the balance between osteoblast‐mediated bone production and osteoclast‐mediated bone resorption. This study aims to investigate the effects of the cannabinoid receptor type 2 (CB2) agonist, GW405833, on interactions between breast cancer cells and osteoblasts as well as its impact on breast cancer‐induced osteoclastogenesis. Materials & Methods MDA‐MB‐231, UMR‐106, RAW 264.7 cells were used to represent breast cancer cells, osteoblast‐like cells and macrophage‐osteoclast precursor cells, respectively. Cell viability was evaluated by MTT assay, and breast cancer cell invasion was assessed by Transwell invasion assay. Tartrate‐resistant acid phosphatase (TRAP) staining was utilized to evaluate osteoclastogenesis. Results Our results demonstrated that GW405833 disrupted MDA‐MB‐231‐induced UMR‐106 cell death and promoted UMR‐106 cell viability. The underlying mechanism of these effects was determined in this study. GW405833 reduced AKT phosphorylation in MDA‐MB‐231 cells without affecting mTOR protein expression or its phosphorylation. Conversely, in UMR‐106 cells, GW405833 induced AKT and mTOR phosphorylated protein. Furthermore, the mTOR inhibitor reversed the GW405833‐induced recovery of UMR‐106 cell viability under MDA‐MB‐231‐derived conditioned media (CM) exposure. These findings underscore the critical role of the AKT/mTOR pathway in mediating GW405833's inhibitory effects on cancer‐bone interactions. Additionally, GW405833 suppressed osteoblast‐enhanced breast cancer cell invasion and the expression of invasion‐related proteins in both cell types, along with reducing osteoclastogenic factors induced by MDA‐MB‐231 CM in UMR‐106 cells and suppressing MDA‐MB‐231 CM‐enhanced osteoclastogenesis in RAW 264.7 cells. Conclusion This study highlights the therapeutic potential of cannabinoid receptor agonist for treating breast cancer bone metastasis and bone‐related complications.

Keywords

• bone interaction
• breast cancer
• CB2 agonist
• metastasis
• osteoblast
• osteoclast