The CXCR4 antagonist plerixafor (AMD3100) promotes proliferation of Ewing sarcoma cell lines in vitro and activates receptor tyrosine kinase signaling

Abstract

BackgroundThe CXCR4 receptor antagonist plerixafor (AMD3100) is raising interest as an anti-cancer agent that disrupts the CXCL12-CXCR4 chemokine – receptor interaction between neoplastic cells and their microenvironment in tumor progression and metastasis. Here, we investigated plerixafor for anti-cancer activity in Ewing sarcoma, a rare and aggressive cancer of bone and soft tissues.MethodsWe used a variety of methods such as cell viability and migration assays, flow cytometry, phospho-tyrosine arrays and western blotting to determine plerixafor effects on five characterized Ewing sarcoma cell lines and a low-passage culture in vitro.ResultsUnexpectedly, plerixafor led to an increase in cell viability and proliferation in standard cell growth conditions, and to chemotactic migration towards plerixafor. Exploring potential molecular mechanisms underlying this effect, we found that Ewing sarcoma cell lines divided into classes of high- and low-level CXCR4 surface expression. Proliferative plerixafor responses were observed in both groups, maintained despite significant CXCR4 down-regulation or inhibition of Gαi-protein signal transduction, and involved activation of multiple receptor tyrosine kinases (DDR2, MERTK, MST1R, NTRK1, RET), the most prominent being platelet-derived growth factor receptor beta (PDGFRB). PDGFRB was activated in response to inhibition of the CXCL12-CXCR4 axis by plerixafor and/or pertussis toxin (Gαi-protein inhibitor). Dasatinib, a multi-kinase inhibitor of both PDGFRB and the CXCR4 downstream kinase SRC, counteracted this activation in some but not all cell lines.ConclusionThese data suggest a feedback interaction between the CXCR4 chemokine receptor and RTK signaling cascades that elicits compensatory cell survival signaling and can shift the net effect of plerixafor towards proliferation. PDGFRB was identified as a candidate driver RTK and potential therapeutic co-target for CXCR4 in Ewing sarcoma. Although as yet limited to in vitro studies, these findings call for further investigation in the cancer – microenvironment interplay in vivo.Electronic supplementary materialThe online version of this article (10.1186/s12964-018-0233-2) contains supplementary material, which is available to authorized users.

JMJD3 promotes the epithelial‑mesenchymal transition and migration of glioma cells via the CXCL12/CXCR4 axis

“…The receptor of CXCL12, CXCR4, has been demonstrated to be widely expressed in a variety of tumors (49,50) and has also been identified to serve crucial roles in the process of cancer growth, invasion and migration (51,52). In the present study, it was examined whether JMJD3 directly upregulated CXCR4 expression in glioma cells.…”

GDF6-CD99 Signaling Regulates Src and Ewing Sarcoma Growth

“…A Src inhibitor, dasatinib, was previously shown to inhibit Ewing sarcoma growth ( Berning et al, 2018 ; Timeus et al, 2008 ), although these studies used higher doses of dasatinib than the dose used to detect the rescue of growth arrest by GDF6 silencing ( Figure 4O , dasatinib used at 50 nM). Dasatinib was also shown to suppress microenvironmental stress-induced migration and tenascin expression in Ewing sarcoma ( Bailey et al, 2016 ; Hawkins et al, 2019 ).…”

Effects of high glucose on proliferation and function of circulating fibrocytes: Involvement of CXCR4/SDF‑1 axis

“…Current studies discovered that the effects of AMD3100 on cell proliferation are considered to be a double-edged sword. It could promote the proliferation of Ewing sarcoma cell lines in vitro (37), but also inhibited cancer cell growth and invasion (38,39). AMD3100 showed no effect on cell proliferation in the present experiment.…”