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Breast Cancer: An Examination of the Potential of ACKR3 to Modify the Response of CXCR4 to CXCL12

Lookup NU author(s): Irene del Molino del Barrio, Georgie Wilkins, Dr Annette Meeson, Professor Simi Ali, Professor John Kirby

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

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.


Publication metadata

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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