Dimerization of CXCR4 in living malignant cells: control of cell migration by a synthetic peptide that reduces homologous CXCR4 interactions
Chemokine receptor CXCR4 (CD184) may play a role in cancer metastasis and is known to form homodimers. However, it is not clear how transmembrane regions (TM) of CXCR4 and receptor homotypic interactions affect the function of CXCR4 in living cells. Using confocal microscopy and flow cytometric anal...
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Veröffentlicht in: | Molecular cancer therapeutics 2006-10, Vol.5 (10), p.2474-2483 |
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Zusammenfassung: | Chemokine receptor CXCR4 (CD184) may play a role in cancer metastasis and is known to form homodimers. However, it is not
clear how transmembrane regions (TM) of CXCR4 and receptor homotypic interactions affect the function of CXCR4 in living cells.
Using confocal microscopy and flow cytometric analysis, we showed that high levels of CXCR4 are present in the cytoplasm,
accompanied by lower expression on the cell surface in CXCR4 transfectants, tumor cells, and normal peripheral blood lymphocytes.
CXCR4 homodimers were detected in tumor cells, both on the cell surface membrane and in the cytoplasm using fluorescence resonance
energy transfer and photobleaching fluorescence resonance energy transfer to measure energy transfer between CXCR4-CFP and
CXCR4-YFP constructs. Disruption of lipid rafts by depletion of cholesterol with methyl-β-cyclodextrin reduced the interaction
between CXCR4 molecules and inhibited malignant cell migration to CXCL12/SDF-1α. A synthetic peptide of TM4 of CXCR4 reduced
energy transfer between molecules of CXCR4, inhibited CXCL12-induced actin polymerization, and blocked chemotaxis of malignant
cells. TM4 also inhibited migration of normal monocytes toward CXCL12. Reduction of CXCR4 energy transfer by the TM4 peptide
and methyl-β-cyclodextrin indicates that interactions between CXCR4s may play important roles in cell migration and suggests
that cell surface and intracellular receptor dimers are appropriate targets for control of tumor cell spread. Targeting chemokine
receptor oligomerization and signal transduction for the treatment of cancer, HIV-1 infections, and other CXCR4 mediated inflammatory
conditions warrants further investigation. [Mol Cancer Ther 2006;5(10):2474–83] |
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ISSN: | 1535-7163 1538-8514 |
DOI: | 10.1158/1535-7163.MCT-05-0261 |