CD24 affects CXCR4 function in pre-B lymphocytes and breast carcinoma cells

Abstract

CD24 is a small, heavily glycosylated cell-surface protein which is linked to the membrane via a glycosyl-phosphatidylinositol (GPI-) anchor and therefore localizes in lipid rafts. CD24 is widely used as a cell-lineage marker for hematopoietic cells. CD24 is also expressed on a variety of human carcinomas, including epithelial ovarian, breast, prostate, colon and lung cancer and has been linked to poor prognosis. Except for its role as a ligand for P-selectin on carcinoma and myeloid cells, a specific function for CD24 has not been determined. Here we show that CD24 affects the function of the chemokine receptor CXCR4. Using isolated CD19-positive bone marrow B cells from CD24-knockout mice and CD24–/– pre-B lymphocytic cell lines, we demonstrate that CD24 expression reduces SDF-1-mediated cell migration and signalling via CXCR4. We observed that the loss of CD24 augmented cellular cholesterol levels and enhanced CXCR4 lipid raft association. Altered chemotactic migration and raft residence was also observed in MDA-MB-231 breast cancer cells expressing high and low levels of CD24 and CXCR4 receptor. MDA-MB-231 cells expressing low levels of CD24 also showed enhanced tumour formation in NOD/SCID mice compared with cells overexpressing CD24. These results demonstrate a novel role for CD24 as a regulator of CXCR4 function that could be relevant for breast cancer growth and metastasis.

Modulation of neuronal CXCR4 by the μ-opioid agonist DAMGO

“…These plasma membrane microdomains, enriched in cholesterol and sphingolipids, concentrate signaling molecules by related receptors (Pike, 2003;Chini and Parenti, 2004). Their composition strongly regulates G-Protein Coupled Receptor (GPCR) function, including that of opioid and chemokine receptors, independently of changes in total protein receptor levels (Popik et al, 2002;Schabath et al, 2006;Xu et al, 2006;Zhao et al, 2006). Importantly, chronic exposure to opioid agonists has been proposed to alter the localization of these signaling molecules (i.e., caveolins, β-arrestins, G proteins and their effectors) within the lipid rafts/caveolae microdomains (Zhao et al, 2006).…”

“…As opioid and chemokine receptors activate similar intracellular pathways, stimulation of neurons with MOR agonists could affect CXCL12 function indirectly, by recruiting/rearranging proteins involved in MOR signaling. Additionally, a recent study in pre-B lymphocytes and breast carcinoma cells (Schabath et al, 2006) demonstrates that exclusion of CXCR4 from membrane lipid rafts, due to reduction in cholesterol levels, impairs the ability of CXCL12 to trigger cell motility via ERK phosphorylation and attenuates tumor growth. An intriguing alternative (that would also depend on colocalization of the two receptors in lipid rafts) is that stimulation with DAMGO or endomorphin-1 induces heterodimerization of MOR with CXCR4, leading to a reduced CXCL12 function as suggested by Fluorescence Resonance Energy Transfer (FRET) studies in cell lines (i.e., HEK293 cells) (Toth et al, 2004).…”

CD24: from A to Z

“…CD24 is broadly overexpressed on many types of tumor tissues, 60,84 including B-cell lymphomas, 85 erythroleukemia, 22 gliomas, 86 small cell lung cancer, 87 esophageal squamous cell carcinoma, 88 hepatocellular carcinoma, 89 cholangiocarcinoma, 90,91 pancreatic adenocarcinoma, 92 urothelial carcinoma, 93,94 ovarian cancer, 95 breast cancer, 28,96,97 primary neuroendocrine carcinomas 98 and prostate carcinomas. 99 Human cancer stem cells appear to have decreased expression of CD24 compared to their offspring; 100,101 however, it is unclear if the same pattern holds in mice.…”

The Bladder Tumor Suppressor Protein TERE1 (UBIAD1)Modulates Cell Cholesterol: Implications for Tumor Progression

“…However, there is also a separate recognition that elevated intracellular cholesterol in non-hormone-dependent tumor cells can contribute to progression based on numerous reports of interference with multiple pathways of growth signaling and apoptosis (Zhuang et al, 2005;Li et al, 2006;Swinnen et al, 2006;Adam et al, 2007;Freeman et al, 2007;Martinez-Abundis et al, 2007;Oh et al, 2007;Christenson et al, 2008;Patra, 2008). The link between intracellular cholesterol and tumor progression has been found in hepatocellular carcinoma, colon, breast, head and neck, and melanoma cancers, either with tumor specimens and/or studies in cancer cell lines (Schabath et al, 2006;Baruthio et al, 2008;Montero et al, 2008). As an essential component for cell membranes required for tumor cell proliferation, and as a central modulator of membrane signaling complexes for growth, oxidative stress management, and apoptosis, altered cholesterol has potential for simultaneously affecting multiple facets of tumor progression.…”