title: Geranylgeranyl diphosphate depletion inhibits breast cancer cell migration.
abstract: 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.
authors.affiliation: Department of Pharmacology, University of Iowa, 51 Newton Road, Iowa City, IA 52242, USA.
authors.forename: Amel
authors.initials: A
authors.lastname: Dudakovic
authors.forename: Huaxiang
authors.initials: H
authors.lastname: Tong
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Hohl
mesh_terms: D053898:Biosynthetic Pathways / Q000187:drug effects; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D004164:Diphosphonates / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D005260:Female; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D013729:Terpenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D004164:Diphosphonates; D011106:Polyisoprenyl Phosphates; D013729:Terpenes; C518651:digeranyl bisphosphonate; D006160:Guanosine Triphosphate; D020742:rhoA GTP-Binding Protein; C002963:geranylgeranyl pyrophosphate