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) 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.
The Journal of clinical investigation. 2023 Jun 22 [Epub ahead of print]
Galina Gritsina, Ka-Wing Fong, Xiaodong Lu, Zhuoyuan Lin, Wanqing Xie, Shivani Agarwal, Dong Lin, Gary E Schiltz, Himisha Beltran, Eva Corey, Colm Morrissey, Yuzhuo Wang, Jonathan C Zhao, Maha Hussain, Jindan Yu
Department of Medicine, Feinberg School of Medicine Northwestern University, Chicago, United States of America., Feinberg School of Medicine Northwestern University, Chicago, United States of America., Department of Urology, Emory University, Atlanta, United States of America., Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, Canada., Department of Chemistry, Northwestern University, Chicago, United States of America., Dana Farber Cancer Institute, Boston, United States of America., Department of Urology, University of Washington, Seattle, United States of America.