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Lookup NU author(s): Irene del Molino del Barrio, Dr Georgie WilkinsORCiD, Dr Annette Meeson, Professor Simi Ali, Emeritus Professor John Kirby
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Upon binding with the chemokine CXCL12, the chemokine receptor CXCR4 has beenshown to promote breast cancer progression. This process, however, can be affected by the expressionof the atypical chemokine receptor ACKR3. Given ACKR3’s ability to form heterodimers withCXCR4, we investigated how dual expression of both receptors differed from their lone expression interms of their signalling pathways. We created single and double CXCR4 and/or ACKR3 Chinesehamster ovary (CHO) cell transfectants. ERK and Akt phosphorylation after CXCL12 stimulation wasassessed and correlated with receptor internalization. Functional consequences in cell migration andproliferation were determined through wound healing assays and calcium flux. Initial experimentsshowed that CXCR4 and ACKR3 were upregulated in primary breast cancer and that CXCR4 andACKR3 could form heterodimers in transfected CHO cells. This co-expression modified CXCR4’s Aktactivation after CXCL12’s stimulation but not ERK phosphorylation (p < 0.05). To assess this signallingdisparity, receptor internalization was assessed and it was observed that ACKR3 was recycled tothe surface whilst CXCR4 was degraded (p < 0.01), a process that could be partially inhibited with aproteasome inhibitor (p < 0.01). Internalization was also assessed with the ACKR3 agonist VUF11207,which caused both CXCR4 and ACKR3 to be degraded after internalization (p < 0.05 and p < 0.001),highlighting its potential as a dual targeting drug. Interestingly, we observed that CXCR4 but notACKR3, activated calcium flux after CXCL12 stimulation (p < 0.05) and its co-expression couldincrease cellular migration (p < 0.01). These findings suggest that both receptors can signal throughERK and Akt pathways but co-expression can alter their kinetics and internalization pathways.
Author(s): del Molino del Barrio I, Wilkins GC, Meeson A, Ali S, Kirby JA
Publication type: Article
Publication status: Published
Journal: International Journal of Molecular Sciences
Year: 2018
Volume: 19
Issue: 11
Online publication date: 14/11/2018
Acceptance date: 08/11/2018
Date deposited: 14/11/2018
ISSN (print): 1661-6596
ISSN (electronic): 1422-0067
Publisher: MDPI AG
URL: https://doi.org/10.3390/ijms19113592
DOI: 10.3390/ijms19113592
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