Chemokine receptor CXCR7 activates Aurora Kinase A and promotes neuroendocrine prostate cancer growth

• Type of Material: Article
• Authors: Galina Gritsina, Northwestern University Feinberg; Ka-wing Fong, Northwestern University Feinberg; Xiaodong Lu, Emory University; Zhuoyuan Lin, Northwestern University Feinberg; Wanqing Xie, Emory University; Shivani Agarwal, Northwestern University Feinberg; Dong Lin, University of British Columbia; Gary E Schiltz, Northwestern University Feinberg; Himisha Beltran, Dana-Farber Cancer Institute; Eva Corey, University of Washington; Colm Morrissey, University of Washington; Yuzhuo Wang, University of British Columbia; Jonathan C Zhao, Emory University; Maha Hussain, Northwestern University Feinberg; Jindan Yu, Emory University
• Language: English
• Date: 2023-08-01
• Publisher: American Society for Clinical Investigation
• Publication Version: Final Published Version
• Copyright Statement: © 2023 Gritsina et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1172/JCI166248
• Title of Journal or Parent Work: The Journal of clinical investigation
• Volume: 133
• Issue: 15
• Keywords: Oncology; Cancer; Cell Proliferation; Signal Transduction; Cell cycle; Humans; Prostatic Neoplasms; Receptors, CXCR; Male; Aurora Kinase A; Cell Line, Tumor
• Research Categories: Chemistry, Biochemistry; Health Sciences, Toxicology; Chemistry, General; Health Sciences, Oncology; Biology, Virology

Abstract

CXCR7 is an atypical chemokine receptor that recruits β-arrestin (ARRB2) and internalizes into clathrin-coated intracellular vesicles where the complex acts as a scaffold for cytoplasmic kinase assembly and signal transduction. Here, we report that CXCR7 was elevated in the majority of prostate cancer (PCa) cases with neuroendocrine features (NEPC). CXCR7 markedly induced mitotic spindle and cell cycle gene expression. Mechanistically, we identified Aurora Kinase A (AURKA), a key regulator of mitosis, as a novel target that was bound and activated by the CXCR7-ARRB2 complex. CXCR7 interacted with proteins associated with microtubules and golgi, and, as such, the CXCR7-ARRB2-containing vesicles trafficked along the microtubules to the pericentrosomal golgi apparatus, where the complex interacted with AURKA. Accordingly, CXCR7 promoted PCa cell proliferation and tumor growth, which was mitigated by AURKA inhibition. In summary, our study reveals a critical role of CXCR7-ARRB2 in interacting and activating AURKA, which can be targeted by AURKA inhibitors to benefit a subset of patients with NEPC.