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Physical interaction with Ephrin B1 promotes CXCR4 intracellular localization and oncogenic potential

ABSTRACT: Chemokine receptor 4 (CXCR4) is a member of the chemokine receptor family that is overexpressed in various cancer types and has been involved in cancer progression and metastasis. In light of recent findings suggesting that intracellular CXCR4 rather than CXCL12-CXCR4-operated signaling promotes cancer cell survival and accumulating evidence indicating that the trafficking and targeting of G protein-coupled receptors (GPCRs) to specific cellular compartments depends on their association with protein partners, we characterized the CXCR4 interactome in HEK-293 cells using an affinity purification-mass spectrometry (AP-MS) strategy. These studies identified Ephrin B1 as a major protein partner of CXCR4 that plays a key role in its intracellular localization and signal transduction.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Kidney Cell

SUBMITTER: Functional Proteomics Platform FPP

LAB HEAD: Philippe Marin

PROVIDER: PXD054221 | Pride | 2026-06-26

REPOSITORIES: Pride

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			Action	DRS
	ONCORNET_160125_CXCR4_E_11A.raw	Raw
	ONCORNET_160125_CXCR4_E_12A.raw	Raw
	ONCORNET_160125_CXCR4_E_13A.raw	Raw
	ONCORNET_160125_CXCR4_E_14A.raw	Raw
	ONCORNET_160125_CXCR4_E_15A.raw	Raw

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Project description:In colorectal cancer, increased expression of the CXC chemokine receptor 4 (CXCR4) has been shown to provoke metastatic disease due to the interaction with its ligand stromal cell-derived factor 1 (SDF-1). Recently, a second SDF-1 receptor, CXCR7, was found to enhance tumor growth in solid tumors. Albeit signaling cascades via SDF-1/CXCR4 have been intensively studied, the significance of the SDF-1/CXCR7-induced intracellular communication triggering malignancy is still only marginally understood. In tumor tissue of 52 colorectal cancer (CRC) patients, we observed that expression of CXCR7 and CXCR4 increased with tumor stage, tumor size, and lymph node infiltration. Asking whether activation of CXCR4 or CXCR7 might result in a similar expression pattern, we performed microarray expression analyses using lentivirally CXCR4- and/or CXCR7-overexpressing SW480 colon cancer cell lines with and without stimulation by SDF-1M-NM-1. Gene regulation via SDF-1M-NM-1/CXCR4 and SDF-1M-NM-1/CXCR7 was completely different and partly antidromic. Expressions of the differentially expressed genes AKR1C3, AXL, EGFR, IGFBP7, IL24, TNNC1, TRIP6 were confirmed by qPCR. Differentially regulated genes were assigned by GO to migration and lipid metabolic processes. Furthermore, using the in silico gene set enrichment analysis we showed for the first time that expressions of miR-217 and miR-218 were increased in CXCR4 and reduced in CXCR7 cells after stimulation with SDF-1M-NM-1. As expected, their putative target mRNAs were inversely expressed. Functional assays exerted that exposure to SDF-1M-NM-1 resulted in strongly amplified invasiveness and chemosensitivity of CXCR4-expressing cells. CXCR7 overexpression led to reduced invasiveness which could only be marginally increased by SDF-1M-NM-1. The CXCR4 antagonist plerixafor significantly reduced invasiveness of CXCR4-overexpressing cells only. Similarly, compared to control cells, CXCR4 cells showed increased sensitivity against 5-FU, while CXCR7 cells were more chemoresistant. These opposing results for CXCR4- or CXCR7-overexpressing colon carcinoma cells demand an unexpected attention in the clinical application of chemokine receptor antagonists like Plerixafor. 24 samples

Project description:In colorectal cancer, increased expression of the CXC chemokine receptor 4 (CXCR4) has been shown to provoke metastatic disease due to the interaction with its ligand stromal cell-derived factor 1 (SDF-1). Recently, a second SDF-1 receptor, CXCR7, was found to enhance tumor growth in solid tumors. Albeit signaling cascades via SDF-1/CXCR4 have been intensively studied, the significance of the SDF-1/CXCR7-induced intracellular communication triggering malignancy is still only marginally understood. In tumor tissue of 52 colorectal cancer (CRC) patients, we observed that expression of CXCR7 and CXCR4 increased with tumor stage, tumor size, and lymph node infiltration. Asking whether activation of CXCR4 or CXCR7 might result in a similar expression pattern, we performed microarray expression analyses using lentivirally CXCR4- and/or CXCR7-overexpressing SW480 colon cancer cell lines with and without stimulation by SDF-1α. Gene regulation via SDF-1α/CXCR4 and SDF-1α/CXCR7 was completely different and partly antidromic. Expressions of the differentially expressed genes AKR1C3, AXL, EGFR, IGFBP7, IL24, TNNC1, TRIP6 were confirmed by qPCR. Differentially regulated genes were assigned by GO to migration and lipid metabolic processes. Furthermore, using the in silico gene set enrichment analysis we showed for the first time that expressions of miR-217 and miR-218 were increased in CXCR4 and reduced in CXCR7 cells after stimulation with SDF-1α. As expected, their putative target mRNAs were inversely expressed. Functional assays exerted that exposure to SDF-1α resulted in strongly amplified invasiveness and chemosensitivity of CXCR4-expressing cells. CXCR7 overexpression led to reduced invasiveness which could only be marginally increased by SDF-1α. The CXCR4 antagonist plerixafor significantly reduced invasiveness of CXCR4-overexpressing cells only. Similarly, compared to control cells, CXCR4 cells showed increased sensitivity against 5-FU, while CXCR7 cells were more chemoresistant. These opposing results for CXCR4- or CXCR7-overexpressing colon carcinoma cells demand an unexpected attention in the clinical application of chemokine receptor antagonists like Plerixafor.

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Physical interaction with Ephrin B1 promotes CXCR4 intracellular localization and oncogenic potential

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