Chemokine receptor CXCR7 activates Aurora Kinase A and promotes neuroendocrine prostate cancer growth
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ABSTRACT:
PROVIDER: PRJNA819102 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18456870.fastq.gz | Fastqsanger.gz | |||
| SRR18456871.fastq.gz | Fastqsanger.gz | |||
| SRR18456872.fastq.gz | Fastqsanger.gz | |||
| SRR18456873.fastq.gz | Fastqsanger.gz | |||
| SRR18456874.fastq.gz | Fastqsanger.gz |
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Project description:CXCR7, an atypical chemokine receptor (ACKR3), is up-regulated in NEPC, and its expression is associated with molecular markers of NEPC and cell proliferation. Transcriptomic analyses revealed a major role of CXCR7 in regulating downstream genes involved in the cell cycle and mitotic spindle. Membrane-bound CXCR7 is known to recruit β-arrestin (ARRB2), and the complex internalizes into clathrin-coated vesicles where they act as a scaffold for cytoplasmic kinase assembly and substrate activation. We identify Aurora Kinase A (AURKA) as a top candidate that is binding to and activated by CXCR7-ARRB2. Immunofluorescence confocal microscopy detected high-density CXCR7, ARRB2, and AURKA in the pericentrosomal area with focal staining of ARRB2 and ARUKA at centrosomes. Mass spectrometry showed that CXCR7 interacts with many proteins associated with intracellular vesicles, microtubules, and Golgi apparatus. CXCR7-ARRB2-containing vesicles traffic along the microtubules to the perinuclear Golgi apparatus, where CXCR7-ARRB2 interacts with AURKA to promote its activation and cell growth. Finally, we showed that pharmacological inhibitors of AURKA abolish CXCR7-driven tumor growth. Our study reveals CXCR7-mediated activation of AURKA and establishes CXCR7 and its downstream kinases as critical targets for therapeutic intervention in CRPC or NEPC patients.
2023-05-14 | GSE199274 | GEO
Project description: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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Project description:The Hippo pathway is crucial in organ size control and tumorigenesis. The dys-regulation of Hippo/YAP axis is vastly observed in gastric cancer, while the effective therapeutic targets for Hippo/YAP axis are still not clear. It is important and urgent to identify reliable drug targets and the underlying mechanisms, which could inhibit the activity of Hippo/YAP axis and gastric cancer progression. In our current study, we demonstrate the membrane receptor CXCR7 (C-X-C chemokine receptor 7) is an important modulator for Hippo/YAP axis. The activation of CXCR7 could stimulate gastric cancer cell progression through Hippo/YAP axis in vitro and in vivo, while pharmaceutical inhibition of CXCR7 via ACT-1004-1239 could block the tumorigenesis in gastric cancer. Molecular studies reveal that the activation of CXCR7 could dephosphorylate YAP, facilitate YAP nuclear accumulation and transcriptional activation in gastric cancer. CXCR7 functions via G-protein Gαq/11 and Rho GTPase to activate YAP activity. Interestingly, ChIP assay shows that YAP could bind to the promoter region of CXCR7 and facilitate its gene transcription, which indicates CXCR7 is both the upstream signaling and downstream target for Hippo/YAP axis in gastric cancer. In general, we identified a novel positive feedback loop between CXCR7 and Hippo/YAP axis, while blockade of CXCR7 could be a plausible strategy for gastric cancer.
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Project description:The standard of care for patients with advanced form of prostate cancer, castration-resistant, now includes enzalutamide, a second generation antiandrogen. However, most of the treated patients will develop resistance to enzalutamide based therapy in around a year, succumbing to lethal disease. Investigating the transcriptome of enzalutamide-resistant prostate cancer cell lines, we identified CXCR7 as one of the most upregulated genes suggesting its role in advanced prostate cancer. CXCR7, known as an atypical G-coupled receptor, is engaged in many physiological and pathological processes. Here we show that in prostate cancer CXCR7 is tightly regulated by androgen receptor (AR), which directly binds to CXCR7 gene promoter and enhancer and represses its transcription. In turn, CXCR7 in prostate cancer reduces enzalutamide toxicity and promotes cell survival and invasiveness. We identified that CXCR7 forms an integral complex with ARRB2 and activates ERK1/2, eliciting pro-survival MAPK pathway. Enzalutamide treatment combined with MAPKK specific inhibitor, trametinib, reversed enzalutamide resistance in prostate cancer in vitro and in vivo. Taken together our findings highlight the critical role of CXCR7 in enzalutamide-resistant prostate cancer and open an avenue for developing novel anti-CXCR7 therapies to improve survival in patients with advanced prostate cancer.
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2012-08-09 | E-GEOD-40017 | biostudies-arrayexpress
Project description:In colorectal cancer, increased expression of the CXC chemokine receptor 4 (CXCR4) has been shown to provoke metastatic disease due to the interaction with its ligand stromal cell-derived factor 1 (SDF-1). Recently, a second SDF-1 receptor, CXCR7, was found to enhance tumor growth in solid tumors. Albeit signaling cascades via SDF-1/CXCR4 have been intensively studied, the significance of the SDF-1/CXCR7-induced intracellular communication triggering malignancy is still only marginally understood. In tumor tissue of 52 colorectal cancer (CRC) patients, we observed that expression of CXCR7 and CXCR4 increased with tumor stage, tumor size, and lymph node infiltration. Asking whether activation of CXCR4 or CXCR7 might result in a similar expression pattern, we performed microarray expression analyses using lentivirally CXCR4- and/or CXCR7-overexpressing SW480 colon cancer cell lines with and without stimulation by SDF-1α. Gene regulation via SDF-1α/CXCR4 and SDF-1α/CXCR7 was completely different and partly antidromic. Expressions of the differentially expressed genes AKR1C3, AXL, EGFR, IGFBP7, IL24, TNNC1, TRIP6 were confirmed by qPCR. Differentially regulated genes were assigned by GO to migration and lipid metabolic processes. Furthermore, using the in silico gene set enrichment analysis we showed for the first time that expressions of miR-217 and miR-218 were increased in CXCR4 and reduced in CXCR7 cells after stimulation with SDF-1α. As expected, their putative target mRNAs were inversely expressed. Functional assays exerted that exposure to SDF-1α resulted in strongly amplified invasiveness and chemosensitivity of CXCR4-expressing cells. CXCR7 overexpression led to reduced invasiveness which could only be marginally increased by SDF-1α. The CXCR4 antagonist plerixafor significantly reduced invasiveness of CXCR4-overexpressing cells only. Similarly, compared to control cells, CXCR4 cells showed increased sensitivity against 5-FU, while CXCR7 cells were more chemoresistant. These opposing results for CXCR4- or CXCR7-overexpressing colon carcinoma cells demand an unexpected attention in the clinical application of chemokine receptor antagonists like Plerixafor.
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Project description:Cxcr7-/- mice die a few hours after birth. All of them display semilunar valves abnormalities, including bicuspid aortic or pulmonary valves. Those defects only become obvious before birth. Keywords: genetic modification
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Project description:<p>Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that may develop de novo or as a mechanism of treatment resistance. N-myc is capable of driving NEPC progression. Alisertib inhibits the interaction between N-myc and its stabilizing factor Aurora-A, inhibiting N-myc signaling, and suppressing tumor growth. In this single arm, multi-institutional open label phase 2 clinical trial of alisertib, sixty men were treated with alisertib 50mg twice daily for 7 days every 21-days. Eligibility included metastatic prostate cancer and at least one: small cell neuroendocrine morphology; ≥50% neuroendocrine marker expression; new liver metastases without PSA progression; elevated serum neuroendocrine markers. The primary endpoint was six-month radiographic progression free survival. Pre-treatment biopsies were evaluated by whole exome and RNA-seq.</p>
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