Document Detail


Rab4 interacts with the human P-glycoprotein and modulates its surface expression in multidrug resistant K562 cells.
MedLine Citation:
PMID:  20209493     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
P-glycoprotein (P-gp) is a plasma membrane glycoprotein that has been signaled as a primary cause of multidrug resistance (MDR) in tumors. We performed a yeast 2-hybrid screen using the C-terminal domain of P-gp and identified 2 small GTPases involved in vesicular trafficking, Rab4 and Rab14, which complex with P-gp. The overexpression of GFP-Rab4, either transiently or stably, but not of Rab14, in K562ADR cells decreased the presence of P-gp in the cell surface. As a result, expression of this GTPase reduced the MDR phenotype of K562ADR cells, by augmenting the intracellular accumulation of daunomycin (DNM). This effect was mimicked by the constitutively active Rab4Q72L mutant, but not by the dominant negative Rab4S27N mutant. Rab4 regulated excocytotic P-gp trafficking to the plasma membrane from intracellular compartments, and this modulation required the interaction of both proteins and the GTPase activity. Noteworthy, K562ADR cells exhibited a significant reduction of Rab4 levels, but not of other Rab GTPases, as compared with the sensitive parental cell line, suggesting that the development of the MDR phenotype in these cells involves upregulation of P-gp and a concomitant downregulation of proteins that regulate its surface expression. Attenuation of endogenous Rab4 levels in K562ADR by RNA interference enhanced the expression of P-gp in the cell surface, and reduced the uptake of DNM. Accordingly, these findings substantiate the notion that modulation of the temporal and spatial distribution of P-gp in cancer cells may be a valid therapeutic strategy to alleviate the MDR phenotype, and signal to Rab4 as a potential target.
Authors:
Clotilde Ferrándiz-Huertas; Asia Fernández-Carvajal; Antonio Ferrer-Montiel
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  International journal of cancer. Journal international du cancer     Volume:  128     ISSN:  1097-0215     ISO Abbreviation:  Int. J. Cancer     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2010-10-28     Completed Date:  2010-12-30     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0042124     Medline TA:  Int J Cancer     Country:  United States    
Other Details:
Languages:  eng     Pagination:  192-205     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 UICC.
Affiliation:
Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, Av de la Universidad s/n, 03202 Elche, Alicante, Spain.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Antibiotics, Antineoplastic / metabolism,  pharmacology
Blotting, Western
Cell Membrane / drug effects,  metabolism*
Daunorubicin / metabolism,  pharmacology
Drug Resistance, Multiple
Drug Resistance, Neoplasm
Endosomes / metabolism
Green Fluorescent Proteins / genetics,  metabolism
HEK293 Cells
Humans
Immunoprecipitation
K562 Cells
Microscopy, Confocal
Molecular Sequence Data
P-Glycoprotein / genetics,  metabolism*
Protein Binding
RNA Interference
Sequence Homology, Amino Acid
Two-Hybrid System Techniques
rab GTP-Binding Proteins / genetics,  metabolism*
rab4 GTP-Binding Proteins / genetics,  metabolism*
Chemical
Reg. No./Substance:
0/Antibiotics, Antineoplastic; 0/P-Glycoprotein; 147336-22-9/Green Fluorescent Proteins; 20830-81-3/Daunorubicin; EC 3.6.1.-/Rab14 protein, human; EC 3.6.1.-/rab GTP-Binding Proteins; EC 3.6.5.2/rab4 GTP-Binding Proteins

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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