Aberrant expression of cortactin in head and neck squamous cell carcinoma cells is associated with enhanced cell proliferation and resistance to the epidermal growth factor receptor inhibitor gefitinib
Aberrant expression of cortactin in head and neck squamous cell carcinoma cells is associated with enhanced cell proliferation and resistance to the epidermal growth factor receptor inhibitor gefitinib
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DOI：
10.1158/0008-5472.can-07-0798
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发表时间：
2007-10-01
期刊：
影响因子：
11.2
通讯作者：
Daly, Roger J.
中科院分区：
文献类型：
--
作者：
Timpson, Paul;Wilson, Ashleigh S.;Daly, Roger J.
CTTN基因(以前被命名为EMS)编码皮质蛋白，皮质蛋白是动态肌动蛋白网络的关键调节因子。CTTN和CCND1都位于染色体11q13，该区域在乳腺癌和头颈部鳞状细胞癌(HNSCC)中常见扩增。在此之前，我们发现了Cortactin在癌细胞中的一个新的作用，通过Cortactin的过度表达可以减弱配体诱导的表皮生长因子(EGF)受体(EGFR)的下调，从而导致持续的信号传递。然而，这如何影响生长因子诱导的细胞反应尚不清楚。在这里，通过调节一组HNSCC细胞系中Cortactin的表达，我们发现在锚定依赖和锚定非依赖的条件下，Cortactin的过表达增强了血清和EGF刺激的增殖，并增加了对Nacikis(脱离诱导的细胞凋亡)的抵抗力。这些效应与细胞外信号调节激酶和/或AKT的激活增加有关。此外，我们报道了Cortactin稳定c-Met受体酪氨酸激酶，并增强肝细胞生长因子诱导的有丝分裂和细胞散射。因此，皮质素可能通过比最初提出的更大范围的受体来调制信号，从而影响各种反应。最后，我们已经确定，皮质肌动蛋白的过度表达，无论是单独的还是与细胞周期蛋白D1上调结合在一起，都会促进对EGFR激酶抑制剂吉非替尼的耐药性。这些发现表明，Cortactin可能在HNSCC的进展中扮演多种角色，应该作为预后、疾病进展和治疗反应的标志来评估，特别是对EGFR导向的药物。
The CTTN gene (formerly designated EMS), encodes cortactin, a key regulator of dynamic actin networks. Both CTTN and CCND1, the latter encoding the cell cycle regulator cyclin D1, reside at chromosomal locus 11q13, a region commonly amplified in breast cancers and head and neck squamous cell carcinoma (HNSCC). Previously, we identified a novel role for cortactin in cancer cells, whereby cortactin overexpression attenuated ligand-induced down-regulation of the epidermal growth factor (EGF) receptor (EGFR), leading to sustained signaling. However, how this affected growth factor-induced cellular responses was unclear. Here, by modulation of cortactin expression in a panel of HNSCC cell lines, we show that cortactin overexpression enhances serum- and EGF_ stimulated proliferation under both anchorage-dependent and anchorage-independent conditions and also increases resistance to anoikis (detachment-induced apoptosis). These effects are associated with increased activation of extracellular signal-regulated kinase and/or AKT. Furthermore, we report that cortactin stabilizes the c-MET receptor tyrosine kinase and enhances hepatocyte growth factor-induced mitogenesis and cell scattering. Therefore, cortactin may modulate signaling by a broader range of receptors than originally proposed and thereby affect a variety of responses. Finally, we have determined that cortactin overexpression, either alone or in combination with cyclin D1 up-regulation, promotes resistance to the EGFR kinase inhibitor gefitinib. These findings indicate that cortactin may play multiple roles in progression of HNSCC and should be evaluated as a marker of prognosis, disease progression, and therapeutic responsiveness, particularly to EGFR-directed agents.