Chemokine receptor CXCR7 activates Aurora Kinase A and promotes neuroendocrine prostate cancer growth
Galina Gritsina, … , Maha Hussain, Jindan Yu
Galina Gritsina, … , Maha Hussain, Jindan Yu
Published June 22, 2023
Citation Information: J Clin Invest. 2023;133(15):e166248. https://doi.org/10.1172/JCI166248.
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Research Article Oncology

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

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.

Authors

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

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Figure 7

CXCR7 increases PCa growth, which is abolished by AURKA inhibition.

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CXCR7 increases PCa growth, which is abolished by AURKA inhibition. (A) ...
(A) CXCR7 KD reduces C4-2B cell proliferation. WST1 assay was performed to measure cell proliferation. CXCR7 KD was confirmed by qRT-PCR. Representative proliferation data from 3 repeated experiments are shown. The data were analyzed by 2-way ANOVA followed by Tukey-corrected multiple-comparison test (mean ± SD, n =3, ****P <0.0001). qRT-PCR data were normalized to GAPDH and then the control condition (mean ± SEM, n =3). Statistical test is based on 1-way ANOVA paired with Dunnett’s multiple comparison test,****P <0.0001. (B) CXCR7 overexpression, confirmed by Western blot, increases 22Rv1 cell proliferation measured by WST-1 assay. Representative proliferation data from 3 repeated experiments are shown here. The data were analyzed by 2-way ANOVA followed by Bonferroni-corrected multiple-comparison test (mean ± SD, n =3, **P <0.01, ****P <0.0001). (C and D) AURKA inhibitor decreases CXCR7-driven cell proliferation in LNCaP (C) and 22Rv1 (D) measured by WST-1 assay. Representative proliferation data from 3 repeated experiments were analyzed by 2-way ANOVA combined with Tukey-corrected multiple-comparison test (mean ± SD, n=3, **P<0.01 ***P<0.001). Western blot confirms a reduction of AURKA and TACC3 phosphorylation under alisertib treatment. (E) AURKA-targeting delays CXCR7-driven tumor growth in vivo. NSG mice were injected s.c. with 1 × 106 of 22Rv1-GFP control or 22Rv1-CXCR7 cells. Tumor size (mm3) was monitored by caliper measurements twice a week. Once tumors reached 100 mm3, mice were randomized to receive either vehicle or alisertib (30 mg/kg) once a day for 21 days for a total of 4 treatment groups, n =4 (GFP-veh), n =5 (GFP-alisertib), n =5 (CXCR7-veh), n =5 (CXCR7-alisertib). Tumor growth data are shown as mean ± SEM. The statistical test is based on 2-way ANOVA combined with a Bonferroni’s-corrected multiple-comparison test (***P <0.001). (F) IHC staining of CXCR7 and pAURKA (T288) of representative tumor samples collected at the endpoint. Scale bars: 20 μm (inset); 100 μm (larger image).