Abstract
Primary glioblastoma is the most frequent human brain tumor in adults and is generally fatal due to tumor recurrence. We previously demonstrated that glioblastoma-initiating cells invade the subventricular zones and promote their radio-resistance in response to the local release of the CXCL12 chemokine. In this work, we show that the mitotic Aurora A kinase (AurA) is activated through the CXCL12–CXCR4 pathway in an ERK1/2-dependent manner. Moreover, the CXCL12–ERK1/2 signaling induces the expression of Ajuba, the main cofactor of AurA, which allows the auto-phosphorylation of AurA.We show that AurA contributes to glioblastoma cell survival, radio-resistance, self-renewal, and proliferation regardless of the exogenous stimulation with CXCL12. On the other hand, AurA triggers the CXCL12-mediated migration of glioblastoma cells in vitro as well as the invasion of the subventricular zone in xenograft experiments. Moreover, AurA regulates cytoskeletal proteins (i.e., Actin and Vimentin) and favors the pro-migratory activity of the Rho-GTPase CDC42 in response to CXCL12. Altogether, these results show that AurA, a well-known kinase of the mitotic machinery, may play alternative roles in human glioblastoma according to the CXCL12 concentration.
Highlights
Primary glioblastoma (GBM), the most common subtype of glioma (WHO grade IV), is the most aggressive human brain tumor in adults
We identify the serine/threonine Aurora A (AurA) mitotic kinase as a new target of the CXCL12 signaling pathway
The phosphoproteome analysis of U87MG cells by mass spectrometry reveals a significant dephosphorylation of Aurora A kinase (AurA) at the Thr288 residue after 1 h of CXCL12 stimulation (12.5 nM)
Summary
Primary glioblastoma (GBM), the most common subtype of glioma (WHO grade IV), is the most aggressive human brain tumor in adults. Gliomagenesis is sustained by rare self-renewing tumor cells, called GBM-initiating cells (GICs), likely involved in tumor growth and recurrence [5]. GICs share similar properties with neural stem cells (NSC) (i.e., spheroids formation and expression of stemness markers) and exhibit the unique ability to initiate tumor development in mouse models [6]. We showed that the SVZ-secreted CXCL12 binds the G-protein coupled receptor (GPCR) CXCR4 at the surface of GICs to promote migration, radio-resistance, and mesenchymal activation [8, 9]. CXCL12 can bind CXCR7 (currently renamed ACKR3), an atypical GPCR unable to induce Gprotein signaling and initially considered as a scavenger receptor. CXCR7 was later shown to signal through Gproteins in GBM cells, thereby opening the controversy [10, 11]
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