Laboratory of Nervous System Diseases and Therapy, GIGA-Neuroscience, University of Liège, Liège, Belgium.
Department of Neurosurgery, CHU of Liège, Liège, Belgium.
Oncogene. 2019 Jan;38(1):73-87. doi: 10.1038/s41388-018-0437-3. Epub 2018 Aug 6.
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.
原发性脑胶质瘤是成年人中最常见的脑肿瘤，由于肿瘤复发，通常是致命的。我们之前证明，脑胶质瘤起始细胞通过局部释放趋化因子 CXCL12 浸润脑室周围区，并促进其放射抗性。在这项工作中，我们表明有丝分裂 Aurora A 激酶（AurA）通过 CXCL12-CXCR4 途径以 ERK1/2 依赖性的方式被激活。此外，CXCL12-ERK1/2 信号诱导 AurA 的主要共因子 Ajuba 的表达，这允许 AurA 的自身磷酸化。我们表明 AurA 有助于神经胶质瘤细胞的存活、放射抗性、自我更新和增殖，而与 CXCL12 的外源性刺激无关。另一方面，AurA 触发神经胶质瘤细胞在体外的 CXCL12 介导的迁移以及异种移植实验中脑室周围区的浸润。此外，AurA 调节细胞骨架蛋白（即肌动蛋白和波形蛋白），并有利于 Rho-GTPase CDC42 的促迁移活性对 CXCL12 的反应。总之，这些结果表明，作为有丝分裂机制的知名激酶，AurA 根据 CXCL12 的浓度可能在人类脑胶质瘤中发挥替代作用。
