Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Simpson Querrey Institute for Epigenetics, Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Oncogene. 2023 Mar;42(11):785-792. doi: 10.1038/s41388-023-02597-7. Epub 2023 Feb 9.
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.
趋化因子及其同源受体构成了一个复杂的信号网络，癌细胞会劫持这个网络，从而导致肿瘤的失控生长和扩散。ACKR3（非典型趋化因子受体 3），传统上称为 CXCR7，在许多癌症中上调，包括晚期前列腺癌，是治疗干预的有前途的靶点。与典型的 G 蛋白偶联受体（如 CXCR4）不同，CXCR7 一旦与配体 CXCL12 结合，就会招募 β-arrestin 而不是 G 蛋白，从而导致 CXCL12 的快速内化和降解，作为一个清道夫受体发挥作用。然而，最近的证据表明，CXCR7 可能不仅仅是 CXCR4 的清道夫或辅助受体，它可能在调节癌症进展中发挥重要作用，其中一些作用独立于 CXCR4 及其配体，如 CXCL12。组成性激活的 CXCR7 与 β-arrestin 结合。这个蛋白复合物内化形成一个支架，用于组装和激活各种细胞质激酶，这些激酶对于细胞存活和肿瘤生长是必需的。在这里，我们回顾和讨论了 CXCR7 调节和功能的最新知识，以及这种新的理解如何指导 CXCR7 抑制剂的开发，重点是前列腺癌。
