Chemokines and their cognate receptors comprise an intricate signaling network that becomes high-jacked by cancer cells for uncontrollable tumor growth and dissemination. ACKR3 (Atypical Chemokine Receptor 3), traditionally called CXCR7, is up-regulated in many cancers, including advanced prostate cancer, and represents promising targets for therapeutic intervention. Unlike typical G protein-coupled receptors such as CXCR4, CXCR7, once bound by its cognate ligand CXCL12, initiates the recruitment of β-arrestin instead of G proteins, and results in rapid internalization and degradation of CXCL12, functioning as a scavenger receptor. However, recent evidence suggests that CXCR7 may be more than a scavenger or auxiliary receptor of CXCR4 and that it may play essential roles in regulating cancer progression, some of which are independent of CXCR4 and its ligands, such as CXCL12. Constitutively active CXCR7 binds to β-arrestin. This protein complex internalizes to form a scaffold for assembling and activating various cytoplasmic kinases necessary for cell survival and tumor growth. Here we review and discuss the up-to-date knowledge on CXCR7 regulation and function and how this new understanding guides the development of CXCR7 inhibitors, focusing on prostate cancer.
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This work was supported in part by the Prostate Cancer Foundation 2017CHAL2008 (to JY), the U.S. National Institutes of Health R01CA172384 (to JY), the Northwestern Prostate SPORE P50CA180995 (to JY), and the NIH/NCI training grant T32CA009560 (to GG).
The authors declare no competing interests.
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Gritsina, G., Yu, J. CXCR7 as a novel therapeutic target for advanced prostate cancer. Oncogene 42, 785–792 (2023). https://doi.org/10.1038/s41388-023-02597-7