Proteasome inhibitor bortezomib (PS-341) enhances RANKL-induced MDA-MB-231 breast cancer cell migration

Abstract

The receptor activator of nuclear factor κB ligand/receptor activator of nuclear factor κB (RANKL/RANK) pathway is crucial for the migration of RANK-expressing cancer cells. The ubiquitin-proteasome protein degradation pathway plays a significant role in tumor metastasis. However, the relationship between these two pathways in tumor cell migration is unclear. In the present study, we explored the effect of the proteasome inhibitor bortezomib (PS-341) on RANKL-induced MDA-MB-231 breast cancer cell migration. Transwell migration assay showed that RANKL-induced MDA-MB-231 cell migration was significantly blocked by the decoy receptor osteoprotegerin (OPG), and was also inhibited by the PI3-K inhibitor LY294002. Western blotting results showed that Akt was rapidly activated by soluble RANKL treatment. PS-341 significantly enhanced RANKL-induced MDA-MB-231 cell migration. Further study showed that the enhancement of migration by PS-341 involved upregulation of activated Akt and RANK. Our results for the first time support the theory that PS-341 treatment may be unsuitable for RANK-positive breast cancer patients.