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.

Expression and potential role of chemokine receptor CXCR4 in human bladder carcinoma cell lines with different metastatic ability

“…The interaction between SdF-1 and cXcr4 activates the specific signaling pathway controlling homing and metastasis. cXcr4 overexpression was found to enhance bladder tumor growth (17). in addition, cXcr4 may enhance invasive signals and metastatic growth in the bladder microenvironment.…”

Role of stromal microenvironment in nonpharmacological resistance of CML to imatinib through Lyn/CXCR4 interactions in lipid rafts

“…Because several reports demonstrated that activated CXCR4 interacts with signaling factors in lipid rafts, 30,31 we investigated the localization of CXCR4 and Lyn in KBM-5 cells by immunoblot analysis of the individual cellular fractions separated by sucrose gradient ( Figure 2). As the marker of lipid rafts, we used the lipid raft-associated protein flotillin-1.…”

Tpl2 induces castration resistant prostate cancer progression and metastasis

“…The activation of FAK and Akt has been reported to be closely associated with cell proliferation, anoikis resistance, migration, invasion and stemness of PC cells. [27][28][29][30][31][40][41][42] CXCR4 leads to the activation of diverse intracellular signaling pathways including the Akt pathway, 34,43,44 and CXCL12 evoked increased expression of FAK and enhanced FAK phosphorylation. 35 Furthermore, it has been established that the tumorigenic and metastatic process of PC is regulated by CXCL12/CXCR4 axis.…”