Document Detail


CXCL12/CXCR4 transactivates HER2 in lipid rafts of prostate cancer cells and promotes growth of metastatic deposits in bone.
MedLine Citation:
PMID:  18337451     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Chemokines and their receptors function in migration and homing of cells to target tissues. Recent evidence suggests that cancer cells use a chemokine receptor axis for metastasis formation at secondary sites. Previously, we showed that binding of the chemokine CXCL12 to its receptor CXCR4 mediated signaling events resulting in matrix metalloproteinase-9 expression in prostate cancer bone metastasis. A variety of methods, including lipid raft isolation, stable overexpression of CXCR4, cellular adhesion, invasion assays, and the severe combined immunodeficient-human bone tumor growth model were used. We found that (a) CXCR4 and HER2 coexist in lipid rafts of prostate cancer cells; (b) the CXCL12/CXCR4 axis results in transactivation of the HER2 receptor in lipid rafts of prostate cancer cells; (c) Src kinase mediates CXCL12/CXCR4 transactivation of HER2 in prostate cancer cells; (d) a pan-HER inhibitor desensitizes CXCR4-induced transactivation and subsequent matrix metalloproteinase-9 secretion and invasion; (e) lipid raft-disrupting agents inhibited raft-associated CXCL12/CXCR4 transactivation of the HER2 and cellular invasion; (f) overexpression of CXCR4 in prostate cancer cells leads to increased HER2 phosphorylation and migratory properties of prostate cancer cells; and (g) CXCR4 overexpression enhances bone tumor growth and osteolysis. These data suggest that lipid rafts on the cell membrane are the key site for CXCL12/CXCR4-induced HER2 receptor transactivation. This transactivation contributes to enhanced invasive signals and metastatic growth in the bone microenvironment.
Authors:
Sreenivasa R Chinni; Hamilto Yamamoto; Zhong Dong; Aaron Sabbota; R Daniel Bonfil; Michael L Cher
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Molecular cancer research : MCR     Volume:  6     ISSN:  1541-7786     ISO Abbreviation:  Mol. Cancer Res.     Publication Date:  2008 Mar 
Date Detail:
Created Date:  2008-03-13     Completed Date:  2008-06-03     Revised Date:  2013-12-30    
Medline Journal Info:
Nlm Unique ID:  101150042     Medline TA:  Mol Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  446-57     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Biotinylation
Bone Neoplasms / pathology,  secondary*
Cell Division
Cell Line, Tumor
Cell Membrane / physiology
Chemokine CXCL12 / genetics,  physiology*
Humans
Male
Membrane Microdomains / physiology*
Neoplasm Invasiveness
Neoplasm Metastasis / pathology*
Prostatic Neoplasms / pathology*
Receptor Cross-Talk
Receptor, erbB-2 / metabolism*
Receptors, CXCR4 / genetics,  physiology*
Transcriptional Activation
Transfection
Grant Support
ID/Acronym/Agency:
P30 CA022453/CA/NCI NIH HHS; R01 DK 067687/DK/NIDDK NIH HHS; R01 DK067687/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/CXCL12 protein, human; 0/CXCR4 protein, human; 0/Chemokine CXCL12; 0/Receptors, CXCR4; EC 2.7.10.1/ERBB2 protein, human; EC 2.7.10.1/Receptor, erbB-2
Comments/Corrections

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