| Gbetagamma signaling promotes breast cancer cell migration and invasion. | |
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MedLine Citation:
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PMID: 20110378 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Signaling through G protein-coupled receptors (GPCRs) promotes breast cancer metastasis. G proteins convey GPCR signals by dissociating into Galpha and Gbetagamma subunits. The aim of the present study was to determine whether blockade of Gbetagamma signaling suppresses breast cancer cell migration and invasion, which are critical components of metastasis. Conditioned media (CM) of NIH-3T3 fibroblasts are widely used as chemoattractants in in vitro cancer metastasis studies. Expression of a Gbetagamma scavenger peptide attenuated NIH-3T3 CM-induced migration and invasion of both metastatic breast cancer MDA-MB-231 and MDA-MB-436 cells by 40 to 50% without effects on cell viability. Migration and invasion of cells in response to NIH-3T3 CM were also blocked by 8-(4,5,6-trihydroxy-3-oxo-3H-xanthen-9-yl)-1-naph-thalene-carboxylic acid) (M119K), a Gbetagamma inhibitor, with maximum inhibition exceeding 80% and half-maximal inhibitory concentration (IC50) values of 1 to 2 microM. M119K also attenuated Rac-dependent formation of lamellipodia, a key structure required for metastasis. Constitutively active Rac1 rescued Gbetagamma blockade-mediated inhibition of breast cancer cell migration, whereas dominant negative Rac1 inhibited cell migration similar to Gbetagamma blockade. Furthermore, M119K suppressed Gi protein-coupled CXC chemokine receptor 4 (CXCR4)-dependent MDA-MB-231 cell migration by 80% with an IC50 value of 1 microM, whereas tyrosine kinase receptor-dependent cell migration was significantly less inhibited. However, CXCR4-dependent inhibition of adenylyl cyclase, a Gialpha-mediated response in MDA-MB-231 cells, was not blocked by M119K but was blocked by pertussis toxin, which selectively inactivates Gialpha. This report is the first to directly demonstrate the role of Gbetagamma in cancer cell migration and invasion and suggests that targeting Gbetagamma signaling pathways may provide a novel strategy for suppressing breast cancer metastasis. |
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Authors:
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Joseph K Kirui; Yan Xie; Dennis W Wolff; Haihong Jiang; Peter W Abel; Yaping Tu |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S. Date: 2010-01-28 |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: 333 ISSN: 1521-0103 ISO Abbreviation: J. Pharmacol. Exp. Ther. Publication Date: 2010 May |
Date Detail:
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Created Date: 2010-04-19 Completed Date: 2010-05-10 Revised Date: 2011-07-28 |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: United States |
Other Details:
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Languages: eng Pagination: 393-403 Citation Subset: IM |
Affiliation:
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Department of Pharmacology, Creighton University School of Medicine, Omaha, Nebraska 68178, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adenylate Cyclase
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drug effects Breast Neoplasms / physiopathology* Cell Line, Tumor Cell Movement / physiology* Cyclic AMP-Dependent Protein Kinases / physiology Cyclohexanes / pharmacology Female GTP-Binding Protein beta Subunits / pharmacology* GTP-Binding Protein gamma Subunits / pharmacology* Humans Microscopy, Fluorescence Neoplasm Invasiveness / physiopathology* Neoplasm Metastasis / drug therapy, physiopathology Peptide Fragments / physiology Pseudopodia / drug effects Receptors, CXCR4 / physiology Recombinant Proteins Signal Transduction / drug effects, physiology Xanthenes / pharmacology rac GTP-Binding Proteins / drug effects, physiology |
| Grant Support | |
ID/Acronym/Agency:
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R011CA125661/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/CXCR4 protein, human; 0/Cyclohexanes; 0/G-protein Beta gamma; 0/GTP-Binding Protein beta Subunits; 0/GTP-Binding Protein gamma Subunits; 0/M119 compound; 0/Peptide Fragments; 0/Receptors, CXCR4; 0/Recombinant Proteins; 0/Xanthenes; EC 2.7.1.-/BARKct protein, recombinant; EC 2.7.11.11/Cyclic AMP-Dependent Protein Kinases; EC 3.6.5.2/rac GTP-Binding Proteins; EC 4.6.1.1/Adenylate Cyclase |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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