Wilke Maria, Göbel Andy, Rauner Martina, Benad-Mehner Peggy, Schütze Norbert, Füssel Susanne, Hadji Peyman, Hofbauer Lorenz C, Rachner Tilman D
Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technical University, Dresden, Germany.
Orthopaedic Center for Musculoskeletal Research, Wuerzburg, Germany.
J Bone Oncol. 2014 Feb 18;3(1):10-7. doi: 10.1016/j.jbo.2014.02.001. eCollection 2014 Mar.
Bone metastases represent common long term complications of patients with breast cancer. Zoledronic acid, an amino-bisphosphonate and mevalonate pathway inhibitor, is an established agent for the treatment of bone metastases. Direct antitumor effects of zoledronic acid have been proposed in breast cancer. Statins are another group of mevalonate pathway inhibitors that have been repeatedly discussed for potential anti-tumor activity. In this study, we tested the hypothesis, whether these agents regulate adhesion of breast cancer cells to extracellular matrix components. Treatment of breast cancer cells with zoledronic acid and atorvastatin, significantly impaired MDA-MB-231 breast cancer cell adhesion on the αvβ3 ligands gelatin and vitronectin, but had no effect on collagen type 1 (α2β1-ligand) and fibronectin (α5β1-ligand). Anti-adhesive effects of zoledronic acid were fully reversed by geranylgeranyl pyrophosphate (GGPP), but not by farnesylpyrophosphate (FPP). Furthermore, effects of zoledronic acid and atorvastatin were mimicked by a specific inhibitor of geranylgeranylation GGTI-298. Functional (using integrin array) and quantitative (using FACS) integrin analyses on MDA-231 cells following zoledronic acid exposure revealed decreased levels of αv and αvβ3 expression. In addition to its effects on integrin mediated adhesion of breast cancer cells, the presence of zoledronic acid caused pronounced morphological changes in MDA-231 cells as seen by F-actin and vinculin rearrangement. Furthermore, phosphorylation of the focal adhesion kinase was inhibited by zoledronic acid. In both cases, changes were fully reversed by GGPP. These results emphasize the role of mevalonate pathway mediated impairment of geranylgeranylation in the anti-adhesive effects of zoledronic acid in breast cancer cells.
骨转移是乳腺癌患者常见的长期并发症。唑来膦酸是一种氨基双膦酸盐和甲羟戊酸途径抑制剂，是治疗骨转移的既定药物。有人提出唑来膦酸在乳腺癌中具有直接抗肿瘤作用。他汀类药物是另一组甲羟戊酸途径抑制剂，其潜在的抗肿瘤活性已被反复讨论。在本研究中，我们检验了这些药物是否调节乳腺癌细胞与细胞外基质成分的黏附这一假设。用唑来膦酸和阿托伐他汀处理乳腺癌细胞，显著损害了MDA-MB-231乳腺癌细胞在αvβ3配体明胶和玻连蛋白上的黏附，但对I型胶原（α2β1配体）和纤连蛋白（α5β1配体）没有影响。唑来膦酸的抗黏附作用被香叶基香叶基焦磷酸（GGPP）完全逆转，但未被法尼基焦磷酸（FPP）逆转。此外，唑来膦酸和阿托伐他汀的作用被香叶基香叶基化特异性抑制剂GGTI-298模拟。对唑来膦酸处理后的MDA-231细胞进行功能性（使用整合素芯片）和定量（使用流式细胞术）整合素分析，发现αv和αvβ3表达水平降低。除了对整合素介导的乳腺癌细胞黏附的影响外，唑来膦酸的存在还导致MDA-231细胞出现明显的形态变化，如F-肌动蛋白和纽蛋白重排所见。此外，唑来膦酸抑制了黏着斑激酶的磷酸化。在这两种情况下，变化都被GGPP完全逆转。这些结果强调了甲羟戊酸途径介导的香叶基香叶基化受损在唑来膦酸对乳腺癌细胞抗黏附作用中的作用。
