Geranylgeranyl diphosphate depletion inhibits breast cancer cell migration
- 18 May 2010
- journal article
- Published by Springer Science and Business Media LLC in Investigational New Drugs
- Vol. 29 (5), 912-920
- https://doi.org/10.1007/s10637-010-9446-y
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.Keywords
This publication has 44 references indexed in Scilit:
- Lipophilic Bisphosphonates as Dual Farnesyl/Geranylgeranyl Diphosphate Synthase Inhibitors: An X-ray and NMR InvestigationJournal of the American Chemical Society, 2009
- Pivaloyloxymethyl-modified isoprenoid bisphosphonates display enhanced inhibition of cellular geranylgeranylationBioorganic & Medicinal Chemistry, 2008
- Role of Rho GTPases in breast cancerFrontiers in Bioscience-Landmark, 2008
- Synthesis of fluorescently tagged isoprenoid bisphosphonates that inhibit protein geranylgeranylationBioorganic & Medicinal Chemistry, 2007
- A phase 2 study of the farnesyltransferase inhibitor tipifarnib in poor-risk and elderly patients with previously untreated acute myelogenous leukemiaBlood, 2006
- Phase III Trial of Gemcitabine Plus Tipifarnib Compared With Gemcitabine Plus Placebo in Advanced Pancreatic CancerJournal of Clinical Oncology, 2004
- Blocking protein geranylgeranylation is essential for lovastatin-induced apoptosis of human acute myeloid leukemia cellsLeukemia, 2001
- Rho GTPases are over-expressed in human tumorsInternational Journal of Cancer, 1999
- PROTEIN PRENYLATION: Molecular Mechanisms and Functional ConsequencesAnnual Review of Biochemistry, 1996
- Role of Protein Modification Reactions in Programming Interactions Between Ras-Related GTPases and Cell MembranesAnnual Review of Cell Biology, 1994