Huang Jian, Hu Jinyue, Bian Xiuwu, Chen Keqiang, Gong Wanghua, Dunlop Nancy M, Howard O M Zack, Wang Ji Ming
Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Science Applications International Corporation-Frederick, National Cancer Institute at Frederick, Frederick, Maryland 21702-1201, USA.
Cancer Res. 2007 Jun 15;67(12):5906-13. doi: 10.1158/0008-5472.CAN-07-0691.
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-phenylalanine, an FPR agonist peptide, rapidly induced EGFR 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 Galphai proteins, and was controlled by Src tyrosine kinase. The transactivation of EGFR contributes to the biological function of FPR in glioblastoma cells because inhibition of EGFR phosphorylation significantly reduced FPR agonist-induced tumor cell chemotaxis and proliferation. Furthermore, depletion of both FPR and EGFR by short interference RNA abolished the tumorigenesis of the glioblastoma 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.
G蛋白偶联的甲酰肽受体（FPR）可介导白细胞对细菌和宿主来源的趋化肽作出反应而发生迁移，它能促进高度恶性的人类胶质母细胞瘤细胞的趋化性、存活及肿瘤发生。由于胶质母细胞瘤细胞可能还表达其他生长信号受体，如表皮生长因子（EGF）受体（EGFR），我们研究了EGFR在FPR信号级联反应中的作用，以及这两种受体如何相互作用以加剧肿瘤生长。我们发现，FPR激动剂肽N-甲酰甲硫氨酰-亮氨酰-苯丙氨酸能迅速诱导胶质母细胞瘤细胞中酪氨酸残基（Tyr）992处的EGFR磷酸化，但不会诱导846、1068或1173位残基的磷酸化，而仅在EGF处理后所有这些残基才会发生磷酸化。肿瘤细胞中FPR激动剂诱导的EGFR磷酸化依赖于FPR以及Gαi蛋白的存在，并受Src酪氨酸激酶的调控。EGFR的反式激活有助于FPR在胶质母细胞瘤细胞中的生物学功能，因为抑制EGFR磷酸化会显著降低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耗尽FPR和EGFR可消除胶质母细胞瘤细胞的肿瘤发生。我们的研究表明，FPR促进胶质母细胞瘤的活性部分是由EGFR的反式激活介导的，两种受体之间的相互作用会加剧肿瘤细胞的恶性表型。因此，同时靶向这两种受体可能会产生比靶向其中一种更好的抗胶质母细胞瘤药物。
