title: CXCL12/CXCR4 transactivates HER2 in lipid rafts of prostate cancer cells and promotes growth of metastatic deposits in bone.
abstract: 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.affiliation: Department of Urology, Wayne State University School of Medicine, Detroit, MI 48201, USA. schinni@med.wayne.edu
authors.forename: Sreenivasa R
authors.initials: SR
authors.lastname: Chinni
authors.forename: Hamilto
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Zhong
authors.initials: Z
authors.lastname: Dong
authors.forename: Aaron
authors.initials: A
authors.lastname: Sabbota
authors.forename: R Daniel
authors.initials: RD
authors.lastname: Bonfil
authors.forename: Michael L
authors.initials: ML
authors.lastname: Cher
mesh_terms: D019921:Biotinylation; D001859:Bone Neoplasms / Q000473:pathology / Q000556:secondary*; D002455:Cell Division; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000502:physiology; D054377:Chemokine CXCL12 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D021962:Membrane Microdomains / Q000502:physiology*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D020239:Receptor Cross-Talk; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: D054377:Chemokine CXCL12; D018719:Erb-b2 Receptor Tyrosine Kinases; D019718:Receptors, CXCR4; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; C508053:ERBB2 protein, human