PDF(Pubmed)
Abstract：
Tumor Treating Fields (TTFields) extend the survival of glioblastoma (GBM) patients by interfering with a broad range of tumor cellular processes. Among these, TTFields disrupt primary cilia stability on GBM cells. Here we asked if concomitant treatment of TTFields with other agents that interfere with GBM ciliogenesis further suppress GBM cell proliferation in vitro. Aurora kinase A (AURKA) promotes both cilia disassembly and GBM growth. Inhibitors of AURKA, such as Alisertib, inhibit cilia disassembly and increase ciliary frequency in various cell types. However, we found that Alisertib treatment significantly reduced GBM cilia frequency in gliomaspheres across multiple patient derived cell lines, and in patient biopsies treated ex vivo. This effect appeared glioma cell-specific as it did not reduce normal neuronal or glial cilia frequencies. Alisertib-mediated depletion of glioma cilia appears specific to AURKA and not AURKB inhibition, and attributable in part to autophagy pathway activation. Treatment of two different GBM patient-derived cell lines with TTFields and Alisertib resulted in a significant reduction in cell proliferation compared to either treatment alone. However, this effect was not cilia-dependent as the combined treatment reduced proliferation in cilia-depleted cell lines lacking, ARL13B, or U87MG cells which are naturally devoid of ARL13B+ cilia. Thus, Alisertib-mediated effects on glioma cilia may be a useful biomarker of drug efficacy within tumor tissue. Considering Alisertib can cross the blood brain barrier and inhibit intracranial growth, our data warrant future studies to explore whether concomitant Alisertib and TTFields exposure prolongs survival of brain tumor-bearing animals in vivo.
摘要：
肿瘤治疗场(TTFields)通过干扰广泛的肿瘤细胞过程来延长成胶质细胞瘤(GBM)患者的存活。其中,TTField破坏GBM细胞上的初级纤毛稳定性。在这里，我们询问TTFelds与其他干扰GBM纤毛发生的药物的伴随治疗是否进一步抑制体外GBM细胞增殖。Aurora激酶A（AURKA）促进纤毛分解和GBM生长。AURKA的抑制剂，比如Alisertib,抑制纤毛分解并增加各种细胞类型的纤毛频率。然而,我们发现，Alisertib治疗显著降低了跨多个患者来源细胞系的胶质细胞球的GBM纤毛频率，和离体治疗的患者活检。这种作用似乎是神经胶质瘤细胞特异性的，因为它不会降低正常的神经元或神经胶质纤毛频率。Alisertib介导的神经胶质瘤纤毛耗竭似乎是AURKA特有的，而不是AURKB抑制，部分归因于自噬途径的激活。用TTField和Alisertib处理两种不同的GBM患者来源的细胞系导致与任一单独处理相比细胞增殖的显著降低。然而,这种作用不是纤毛依赖性的，因为联合治疗减少了纤毛缺失细胞系的增殖，ARL13B,或天然缺乏ARL13B+纤毛的U87MG细胞。因此，Alisertib介导的对神经胶质瘤纤毛的作用可能是肿瘤组织内药物功效的有用生物标志物。考虑到Alisertib可以穿过血脑屏障并抑制颅内生长，我们的数据保证了未来的研究，以探讨是否同时暴露Alisertib和TTFields延长脑肿瘤携带动物的体内生存期。
