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

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

doi:10.1172/JCI166248

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

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

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

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.

Original language	English
Article number	e166248
Journal	Journal of Clinical Investigation
Volume	133
Issue number	15
DOIs	https://doi.org/10.1172/JCI166248
State	Published - Aug 1 2023

Bibliographical note

Publisher Copyright:
Copyright: © 2023, Gritsina et al.

Funding

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 Center Support Grant (NCI P30CA060553). Northwestern Proteomics is also supported by the National Resource for Translational 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 xenograft 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) Conflict of interest: EC has University of Washington institutional SRA funding from Janssen Research, Bayer Pharmaceuticals, Forma Pharmaceuticals, MacroGenics, Kronos Bio, Foghorn, Astra Zeneca, Gilead, and AbbVie not related to the work in the manuscript. HB has received research funding from Millennium. Copyright: © 2023, Gritsina et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. Submitted: October 13, 2022; Accepted: June 15, 2023; Published: August 1, 2023. Reference information: J Clin Invest. 2023;133(15):e166248. https://doi.org/10.1172/JCI166248.

Funders	Funder number
National Resource for Translational and Developmental Proteomics	P41GM108569
Taplin Biological Mass Spectrometry Facility at Harvard Medical School
National Institutes of Health (NIH)	T32 CA009560, P50CA180995, R01CA172384, R50CA211271
National Institutes of Health (NIH)
American Cancer Society-Michigan Cancer Research Fund	P20GM121327, IRG-19-140-31, R03CA256230
American Cancer Society-Michigan Cancer Research Fund
National Childhood Cancer Registry – National Cancer Institute	P30CA060553
National Childhood Cancer Registry – National Cancer Institute
Prostate Cancer Foundation	2017CHAL2008
Prostate Cancer Foundation
Northwestern Polytechnical University
Taiwan Forestry Research Institute	1109
Taiwan Forestry Research Institute
Canadian Institutes of Health Research	180554, 173338, 186331, 153081
Canadian Institutes of Health Research
European Commission

ASJC Scopus subject areas

General Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1172/JCI166248

Cite this

Gritsina, G., Fong, K. W., Lu, X., Lin, Z., Xie, W., Agarwal, S., Lin, D., Schiltz, G. E., Beltran, H., Corey, E., Morrissey, C., Wang, Y., Zhao, J. C., Hussain, M., & Yu, J. (2023). Chemokine receptor CXCR7 activates Aurora Kinase A and promotes neuroendocrine prostate cancer growth. Journal of Clinical Investigation, 133(15), Article e166248. https://doi.org/10.1172/JCI166248

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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.",

author = "Galina Gritsina and Fong, {Ka Wing} and Xiaodong Lu and Zhuoyuan Lin and Wanqing Xie and Shivani Agarwal and Dong Lin and Schiltz, {Gary E.} and Himisha Beltran and Eva Corey and Colm Morrissey and Yuzhuo Wang and Zhao, {Jonathan C.} and Maha Hussain and Jindan Yu",

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AU - Gritsina, Galina

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AU - Lu, Xiaodong

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AU - Xie, Wanqing

AU - Agarwal, Shivani

AU - Lin, Dong

AU - Schiltz, Gary E.

AU - Beltran, Himisha

AU - Corey, Eva

AU - Morrissey, Colm

AU - Wang, Yuzhuo

AU - Zhao, Jonathan C.

AU - Hussain, Maha

AU - Yu, Jindan

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N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

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