Mutant epidermal growth factor receptor displays increased signaling through the phosphatidylinositol-3 kinase/AKT pathway and promotes radioresistance in cells of astrocytic origin
Mutant epidermal growth factor receptor displays increased signaling through the phosphatidylinositol-3 kinase/AKT pathway and promotes radioresistance in cells of astrocytic origin
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DOI：
10.1038/sj.onc.1207602
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发表时间：
2004-06-03
期刊：
影响因子：
8
通讯作者：
Shu, HKG
中科院分区：
文献类型：
--
作者：
Li, B;Yuan, M;Shu, HKG
表皮生长因子受体（EGFR）的扩增和突变是恶性胶质瘤的常见特征。在这些肿瘤中观察到的最常见的突变涉及外显子2-7的缺失，导致受体的组成型活性形式（EGFRvIII或deltaEGFR）。由于EGFRvIII主要在神经胶质瘤中发现，在肉瘤中尚未报道，我们比较了这种改变的受体在永生化的原代星形胶质细胞和成纤维细胞中的作用。虽然EGFRvIII在两种细胞类型中显示配体非依赖性自磷酸化，但下游信号传导不同。虽然EGFRvIII增加了星形胶质细胞和成纤维细胞的增殖能力，这与这些细胞中ERK的激活一致，但EGFRvIII仅在永生化星形胶质细胞中激活AKT。星形胶质细胞中的EGFRvIII表达也导致该细胞类型的放射抗性增加。此外，特异性抑制磷脂酰肌醇-3激酶（PI-3 K）与LY 294002恢复放射抗性表型的永生化星形胶质细胞。因此，在表达EGFRvIII的星形胶质细胞中PI-3 K/AKT的选择性激活似乎是观察到的放射抗性增加的原因。EGFRvIII激活PI-3 K下游信号的不同能力可以解释为什么这种突变受体在恶性胶质瘤中是如此突出的病变，但在其他肿瘤类型中却不常见，即使是EGFR信号传导具有突出作用的肿瘤。
Amplification and mutation of the epidermal growth factor receptor (EGFR) are common features of malignant gliomas. The most frequent mutation seen in these tumors involves deletion of exon 2-7 resulting in a constitutively active form of the receptor (EGFRvIII, or deltaEGFR). Since EGFRvIII is found primarily in gliomas and has not been reported in sarcomas, we compared the effects of this altered receptor in immortalized primary astrocytes and fibroblasts. While EGFRvIII displayed ligand-independent autophosphorylation in both cell types, downstream signaling differed. While EGFRvIII increased the proliferative capacity of both astrocytes and fibroblasts consistent with activation of ERK in these cells, EGFRvIII activated AKT only in the immortalized astrocytes. EGFRvIII expression in astrocytes also led to increased radioresistance in that cell type. Furthermore, specific inhibition of phosphotidylinositol-3 kinase (PI-3K) with LY294002 reverted the radioresistant phenotype in the immortalized astrocytes. Thus, selective activation of PI-3K/AKT in astrocytes expressing EGFRvIII appears to be responsible for the observed increase in radio resistance. EGFRvIII's differential ability to activate the PI-3K downstream signal may explain why this mutant receptor is such a prominent lesion in malignant gliomas but less often seen in other tumor types, even those where EGFR signaling has a prominent role.