Transactivation of the Epidermal Growth Factor Receptor by Formylpeptide Receptor Exacerbates the Malignant Behavior of Human Glioblastoma Cells

Abstract

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 GAi 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. [Cancer Res 2007;67(12):5906-13]

Annexin 1 Released by Necrotic Human Glioblastoma Cells Stimulates Tumor Cell Growth through the Formyl Peptide Receptor 1

“…Because depletion of either FPR1 1,12 or Anx A1 reduced the growth of transplanted tumors formed by U87 GBM cells, and double knocking down both molecules even further reduced the capacity of GBM cells to form tumors in vivo, the axis of Anx A1 and FPR1 in GBM cells should constitute molecular targets for the development of novel anti-GBM therapy.…”

“…1,12 We therefore examined whether NecSup also possessed tumor cell growth stimulating activity. Figure 3A shows that NecSup enhanced U87 GBM cell proliferation.…”

Chemokines in cancer related inflammation

“…Cancer-associated fibroblasts (CAF) have been extensively studied in more recent years and found to be a source of CCL2, CCL5 and CXC-chemokines; indeed there is a bidirectional crosstalk between tumor cells and CAF [118,119]. A positive correlation has been reported between stromal expression of CXCL12 and high tumor proliferative index [120] and, in another study, with proliferation of CD44 + CD24− breast cancer stem cells [83]. A notable example was provided in breast cancer, where tumor cells induced CCL5 secretion in newly recruited mesenchymal cells; stromal-derived CCL5 then interacted with CCR5-positive tumor cells enhancing their growth in vivo and metastatic ability [116].…”

“…In human glioblastoma cells, activation of the formyl-peptide chemotactic receptor (a non-chemokine receptor) resulted in the phosphorylation of Epidermal Growth Factor Receptor. Silencing of both receptors abolished tumor formation in nude mice [83].…”

The G-protein-coupled formylpeptide receptor FPR confers a more invasive phenotype on human glioblastoma cells

“…Vascular endothelial growth factor production and microvascular density Flow cytometry, RT -PCR, immunocytochemistry tumourigenesis, histology, cell proliferation and tumour colony formation were performed as reported earlier (Huang et al, 2007(Huang et al, , 2008b.…”