Geranylgeranyl diphosphate depletion inhibits breast cancer cell migration
Geranylgeranyl diphosphate depletion inhibits breast cancer cell migration
复制标题
DOI：
10.1007/s10637-010-9446-y
复制
发表时间：
2011-10-01
影响因子：
3.4
通讯作者：
Hohl, Raymond J.
中科院分区：
文献类型：
--
作者：
Dudakovic, Amel;Tong, Huaxiang;Hohl, Raymond J.
本研究的目的是确定香叶基香叶基二磷酸合酶抑制，从而香叶基香叶基二磷酸消耗，是否干扰乳腺癌细胞迁移。双膦酸二香叶酯是一种特异性的香叶基香叶基二磷酸合酶抑制剂。我们证明，二香叶基二膦酸耗尽香叶基香叶基二磷酸和抑制蛋白质香叶基香叶基化在MDA-MB-231细胞。与GGT酶I抑制剂GGTI-286类似，双磷酸二香叶酯显著抑制MDA-MB-231细胞的迁移，如transwell测定所测量的。类似地，如通过大规模数字细胞分析系统显微镜所测量的，双膦酸二香叶酯以时间依赖性方式降低MDA-MB-231细胞的运动性。双膦酸二香叶酯毒性轻微，不诱导细胞凋亡。用双膦酸二香叶酯处理MDA-MB-231细胞减少了膜，同时增加了细胞溶质RhoA定位。此外，双膦酸二香叶酯增加了MDA-MB-231细胞中的RhoA GTP结合。通过外源性添加香叶基香叶基二磷酸证实了二膦酸二香叶基酯抑制香叶基香叶基二磷酸合酶的特异性。在MDA-MB-231细胞中，香叶基香叶基二磷酸的加入阻止了二香叶基二膦酸盐对迁移、RhoA定位和GTP与RhoA结合的影响。这些研究表明，香叶基香叶基二磷酸合酶抑制剂是一种新的方法来干扰癌细胞迁移。
The objective of this study was to determine whether geranylgeranyl diphosphate synthase inhibition, and therefore geranylgeranyl diphosphate depletion, interferes with breast cancer cell migration. Digeranyl bisphosphonate is a specific geranylgeranyl diphosphate synthase inhibitor. We demonstrate that digeranyl bisphosphonate depleted geranylgeranyl diphosphate and inhibited protein geranylgeranylation in MDA-MB-231 cells. Similar to GGTI-286, a GGTase I inhibitor, digeranyl bisphosphate significantly inhibited migration of MDA-MB-231 cells as measured by transwell assay. Similarly, digeranyl bisphosphonate reduced motility of MDA-MB-231 cells in a time-dependent manner as measured by large scale digital cell analysis system microscopy. Digeranyl bisphosphonate was mildly toxic and did not induce apoptosis. Treatment of MDA-MB-231 cells with digeranyl bisphosphonate decreased membrane while it increased cytosolic RhoA localization. In addition, digeranyl bisphosphonate increased RhoA GTP binding in MDA-MB-231 cells. The specificity of geranylgeranyl diphosphonate synthase inhibition by digeranyl bisphosphonate was confirmed by exogenous addition of geranylgeranyl diphosphate. Geranylgeranyl diphosphate addition prevented the effects of digeranyl bisphosphonate on migration, RhoA localization, and GTP binding to RhoA in MDA-MB-231 cells. These studies suggest that geranylgeranyl diphosphate synthase inhibitors are a novel approach to interfere with cancer cell migration.