Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, PR China.
Mol Med Rep. 2012 Feb;5(2):580-4. doi: 10.3892/mmr.2011.678. Epub 2011 Nov 16.
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.
核因子-κB 受体激活剂配体/核因子-κB 受体激活剂（RANKL/RANK）通路对于 RANK 表达的癌细胞的迁移至关重要。泛素-蛋白酶体蛋白降解途径在肿瘤转移中起着重要作用。然而，这两条途径在肿瘤细胞迁移中的关系尚不清楚。在本研究中，我们探讨了蛋白酶体抑制剂硼替佐米（PS-341）对 RANKL 诱导的 MDA-MB-231 乳腺癌细胞迁移的影响。Transwell 迁移实验表明，诱饵受体骨保护素（OPG）显著阻断了 RANKL 诱导的 MDA-MB-231 细胞迁移，PI3-K 抑制剂 LY294002 也抑制了迁移。Western blot 结果表明，可溶性 RANKL 处理可迅速激活 Akt。PS-341 显著增强了 RANKL 诱导的 MDA-MB-231 细胞迁移。进一步的研究表明，PS-341 增强迁移涉及激活的 Akt 和 RANK 的上调。我们的研究结果首次支持 PS-341 治疗可能不适合 RANK 阳性乳腺癌患者的理论。
