Aurora A(AURKA)是一种丝氨酸/苏氨酸激酶,是Aurora激酶家族的成员之一。Aurora激酶家族包括Aurora A、Aurora B和Aurora C三种激酶,它们在细胞周期调控中发挥着关键作用。Aurora A主要参与细胞周期的G2/M转换和有丝分裂,通过磷酸化下游底物来调节细胞的基本过程。AURKA位于染色体20上,在许多人类癌症中,如乳腺癌,其基因被扩增或过表达。AURKA不仅存在于细胞质中,还能进入细胞核,在核内与其他转录因子,如FoxM1、C-Myc和NF-κB等协同作用,促进癌基因的转录和表达,维持致癌信号,如N-Myc和Wnt信号。此外,AURKA还在控制癌症的增殖、侵袭、细胞周期调节和癌症干细胞的自我更新中发挥着重要作用。
AURKA在多种肿瘤中发挥着致癌作用,如脑膜瘤、头颈鳞状细胞癌(HNSCC)、肝细胞癌(HCC)和神经内分泌前列腺癌等。例如,在脑膜瘤中,AURKA表达上调,增强其恶性特征,并通过与kelch样ECH关联蛋白1(KEAP1)直接相互作用和磷酸化,激活核因子红细胞2相关因子2(NFE2L2/NRF2)及其靶基因的转录,从而抑制erastin诱导的铁死亡。在HNSCC中,AURKA表达上调,与铜死亡和铁死亡相关,且AURKA表达升高与HNSCC患者的预后不良相关。此外,AURKA在细胞核内还具有非激酶活性,如通过调节RNA剪接和染色质修饰等方式影响基因表达。
目前,针对AURKA的抑制剂已被开发,并在临床试验中评估。然而,患者对AURKA抑制剂的总体反应率并不理想,这提示我们关注AURKA的非激酶活性。最近的研究表明,AURKA的核功能及其非激酶活性可能是抗癌治疗的潜在靶点。例如,在神经内分泌前列腺癌中,趋化因子受体CXCR7激活AURKA,促进肿瘤生长,而AURKA抑制剂可以减轻这一作用。在胰腺癌中,AURKA抑制剂CCT137690可以诱导坏死样细胞死亡,并减缓肿瘤生长。
总之,AURKA作为一种重要的丝氨酸/苏氨酸激酶,在细胞周期调控和肿瘤发生中发挥着关键作用。AURKA在多种肿瘤中表达上调,具有致癌作用,并且具有非激酶活性。针对AURKA的抑制剂已在临床试验中评估,但患者对其反应率有限。进一步研究AURKA的核功能和非激酶活性,有助于我们更深入地了解AURKA在肿瘤发生中的作用机制,为开发更有效的抗癌治疗策略提供理论基础[1,2,3,4,5,6,7,8,9,10]。
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