Imatinib and Nilotinib increase glioblastoma cell invasion via Abl-independent stimulation of p130Cas and FAK signalling.
Imatinib and Nilotinib increase glioblastoma cell invasion via Abl-independent stimulation of p130Cas and FAK signalling.
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DOI：
10.1038/srep27378
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发表时间：
2016-06-13
影响因子：
4.6
通讯作者：
Frankel P
中科院分区：
文献类型：
--
作者：
Frolov A;Evans IM;Li N;Sidlauskas K;Paliashvili K;Lockwood N;Barrett A;Brandner S;Zachary IC;Frankel P
伊马替尼是第一个被批准用于临床的靶向酪氨酸激酶抑制剂，并且仍然是费城染色体（Ph+）阳性慢性髓细胞性白血病的一线治疗。我们发现，用伊马替尼和密切相关的药物尼洛替尼治疗人多形性胶质母细胞瘤（GBM）肿瘤细胞，显著增加了p130Cas、粘着斑激酶（FAK）和下游衔接蛋白桩蛋白（PXN）的酪氨酸磷酸化，从而增强了细胞迁移和侵袭。伊马替尼和尼洛替尼诱导的酪氨酸磷酸化依赖于p130Cas表达和FAK活性，不依赖于已知的伊马替尼靶点，包括Abl、血小板衍生生长因子受体β（PDGFRβ）和胶原受体DDR1。伊马替尼和尼洛替尼处理增加了胶原蛋白中的二维细胞迁移和三维放射状球体侵入。此外，沉默p130Cas和抑制FAK活性都强烈降低伊马替尼和尼洛替尼刺激的侵袭。重要的是，伊马替尼和尼洛替尼增加了从人脑胶质瘤活检分离的干细胞系中p130Cas、FAK、PXN的酪氨酸磷酸化和放射状球体侵袭。这些发现确定了GBM细胞中两种成熟的癌症一线疗法的新作用机制，从而增强了肿瘤细胞的运动性。
Imatinib was the first targeted tyrosine kinase inhibitor to be approved for clinical use, and remains first-line therapy for Philadelphia chromosome (Ph+)-positive chronic myelogenous leukaemia. We show that treatment of human glioblastoma multiforme (GBM) tumour cells with imatinib and the closely-related drug, nilotinib, strikingly increases tyrosine phosphorylation of p130Cas, focal adhesion kinase (FAK) and the downstream adaptor protein paxillin (PXN), resulting in enhanced cell migration and invasion. Imatinib and nilotinib-induced tyrosine phosphorylation was dependent on expression of p130Cas and FAK activity and was independent of known imatinib targets including Abl, platelet derived growth factor receptor beta (PDGFRβ) and the collagen receptor DDR1. Imatinib and nilotinib treatment increased two dimensional cell migration and three dimensional radial spheroid invasion in collagen. In addition, silencing of p130Cas and inhibition of FAK activity both strongly reduced imatinib and nilotinib stimulated invasion. Importantly, imatinib and nilotinib increased tyrosine phosphorylation of p130Cas, FAK, PXN and radial spheroid invasion in stem cell lines isolated from human glioma biopsies. These findings identify a novel mechanism of action in GBM cells for two well established front line therapies for cancer resulting in enhanced tumour cell motility.