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.

Document Type

Article

Publication Date

8-2023

Notes/Citation Information

© 2023, Gritsina et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

Digital Object Identifier (DOI)

https://doi.org/10.1172/JCI166248

Funding Information

The following Northwestern core facilities contributed to this work: Center for Comparative Medicine, Mouse Histology and Phenotyping Laboratory, Pathology Core Facility, Sanger Sequencing Facility, and the Center for Advanced Microscopy supported by the Robert H Lurie Comprehensive Cancer Cen- ter Support Grant (NCI P30CA060553). Northwestern Pro- teomics is also supported by the National Resource for Trans- lational and Developmental Proteomics grant (P41GM108569). Mass spectrometry analysis was done by Taplin Biological Mass Spectrometry Facility at Harvard Medical School. The authors thank Huiping Liu (Northwestern University) for providing male NSG mice from their in-house breeding for the xeno- graft studies. This work was supported in part by the Prostate Cancer Foundation 2017CHAL2008 (to JY, JCZ, GES, EC, and MH), the U.S. National Institutes of Health R01CA172384 (to JY), R50CA211271 (to JCZ), the Northwestern Prostate SPORE P50CA180995 (to JY and MH), the NIH/NCI training grant T32 CA009560 (to GG), the American Cancer Society IRG-19-140- 31 (to KF), NIH P20GM121327 (to KF), and NIH R03CA256230 (to KF). PNW Prostate Cancer SPORE P50CA097186, and P01CA163227, supported establishment and characterization of the LuCaP PDX models. LTL PDX models were supported in part by CIHR (#153081, #173338, #180554, #186331, to YZW), and TFRI (#1109, to YZW)

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