Transactivation of the epidermal growth factor receptor by formylpeptide receptor exacerbates the malignant behavior of human glioblastoma cells
Transactivation of the epidermal growth factor receptor by formylpeptide receptor exacerbates the malignant behavior of human glioblastoma cells
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DOI：
10.1158/0008-5472.can-07-0691
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发表时间：
2007-06-15
期刊：
影响因子：
11.2
通讯作者：
Wang, Ji Ming
中科院分区：
文献类型：
--
作者：
Huang, Jian;Hu, Jinyue;Wang, Ji Ming
G 蛋白偶联甲酰肽受体 (FPR) 介导白细胞迁移以响应细菌和宿主来源的趋化肽，促进高度恶性的人胶质母细胞瘤细胞的趋化性、存活和肿瘤发生。由于胶质母细胞瘤细胞还可能表达其他生长信号受体，例如表皮生长因子 (EGF) 受体 (EGFR)，因此我们研究了 EGFR 在 FPR 信号级联中的作用以及两个受体如何相互作用以加剧肿瘤生长。我们发现，在胶质母细胞瘤细胞中，N-甲酰基-甲硫氨酰-亮氨酰-苯丙氨酸（一种 FPR 激动剂肽）可快速诱导 FGFR 在酪氨酸残基 (Tyr) 992 处磷酸化，但不会在胶质母细胞瘤细胞中诱导残基 846、1068 或 1173 处磷酸化，而所有这些残基仅在 EGF 处理后就会被磷酸化。肿瘤细胞中 FPR 激动剂诱导的 EGFR 磷酸化依赖于 FPR 以及 G α i 蛋白的存在，并受 Src 酪氨酸激酶控制。 FGFR 的反式激活有助于胶质母细胞瘤细胞中 FPR 的生物学功能，因为抑制 EGFR 磷酸化可显着降低 FPR 激动剂诱导的肿瘤细胞趋化性和增殖。此外，通过短干扰RNA消除FPR和EGFR，消除了胶质母细胞瘤细胞的肿瘤发生。我们的研究表明，FPR 的胶质母细胞瘤促进活性部分是由 EGFR 的反式激活介导的，两种受体之间的串扰加剧了肿瘤细胞的恶性表型。因此，针对这两种受体可能会产生优于针对其中一种受体的抗胶质母细胞瘤药物。
The G protein-coupled formylpeptide receptor (FPR), which mediates leukocyte migration in response to bacterial and host-derived chemotactic peptides, promotes the chemotaxis, survival, and tumorigenesis of highly malignant human glioblastoma cells. Because glioblastoma cells may also express other receptors for growth signals, such as the epidermal growth factor (EGF) receptor (EGFR), we investigated the role of EGFR in the signaling cascade of FPR and how two receptors cross-talk to exacerbate tumor growth. We found that N-formyl-methionyl-leucyl-phenylatanine, an FPR agonist peptide, rapidly induced FGFR phosphorylation at tyrosine residue (Tyr) 992, but not residues 846, 1068, or 1173, in glioblastoma cells, whereas all these residues were phosphorylated after only EGF treatment. The FPR agonist-induced EGFR phosphorylation in tumor cells was dependent on the presence of FPR as well as G alpha i proteins, and was controlled by Src tyrosine kinase. The transactivation of FGFR contributes to the biological function of FPR in glioblastoma cells because inhibition of EGFR phosphorylation significantly reduced FPR agonist-induced tumor cell chernotaxis and proliferation. Furthermore, depletion of both FPR and EGFR by short interference RNA abolished the tumorigenesis of the glioblastorna cells. Our study indicates that the glioblastoma-promoting activity of FPR is mediated in part by transactivation of EGFR and the cross-talk between two receptors exacerbates the malignant phenotype of tumor cells. Thus, targeting both receptors may yield antiglioblastoma agents superior to those targeting one of them.