Highly malignant human glioblastoma and anaplastic astrocytoma specimens express a formylpeptide receptor FPR, which is normally expressed in myeloid cells and results in their chemotaxis and activation induced by bacterial peptides. Screening of human glioma cell lines revealed that FPR was expressed only in more highly malignant glioma cell lines. FPR expressed in glioblastoma cell lines mediates tumor cell migration, proliferation and production of angiogenic factors, vascular endothelial growth factor (VEGF) and IL-8 (CXCL8), in response to agonist molecules released by necrotic tumor cells. Stimulation of FPR in glioblastoma cells also activates the receptor for epidermal growth factor (EGFR) by a signal transduction cascade that increases the phosphorylation of a selected tyrosine residue in the intracellular domain of EGFR. This transactivation of EGFR by FPR accounts for part of the capacity of FPR to mediate tumor cell migration and activation. Depletion of either FPR or EGFR in tumor cells by small interference (si) RNA each reduced the capacity of the tumor cells to form actively growing tumors in nude mice. However, depletion of both receptors completely abolishes the tumorigenicity of glioblastoma cells. Mechanistic studies of the regulation of aberrantly expressed FPR in glioblastoma cells revealed increased methylation in the promoter region of p53 gene, which reduced the capacity of p53 to repress FPR in tumor cells. This was reversed by reduction of methylation in p53 gene promoter and differentiation of glioblastoma cells into lesser malignant phenotype. Thus, FPR plays an important role in promoting glioblastoma progression and is a molecular targets for the design of novel anti-glioblastoma therapeutics.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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Chen, Keqiang; Wang, Ji Ming; Yuan, Ruoxi et al. (2016) Tissue-resident dendritic cells and diseases involving dendritic cell malfunction. Int Immunopharmacol 34:1-15
De Buck, Mieke; Gouwy, Mieke; Wang, Ji Ming et al. (2016) The cytokine-serum amyloid A-chemokine network. Cytokine Growth Factor Rev 30:55-69
Guo, Zheng-Jun; Yang, Lang; Qian, Feng et al. (2016) Transcription factor RUNX2 up-regulates chemokine receptor CXCR4 to promote invasive and metastatic potentials of human gastric cancer. Oncotarget 7:20999-1012
Zhang, Liang; Wang, Huanyu; Yang, Tianshu et al. (2016) Formylpeptide receptor 1 mediates the tumorigenicity of human hepatocellular carcinoma cells. Oncoimmunology 5:e1078055
Yoshimura, Teizo; Imamichi, Tomozumi; Weiss, Jonathan M et al. (2016) Induction of Monocyte Chemoattractant Proteins in Macrophages via the Production of Granulocyte/Macrophage Colony-Stimulating Factor by Breast Cancer Cells. Front Immunol 7:2
Li, Liangzhu; Chen, Keqiang; Xiang, Yi et al. (2016) New development in studies of formyl-peptide receptors: critical roles in host defense. J Leukoc Biol 99:425-35
Drechsler, Maik; de Jong, Renske; Rossaint, Jan et al. (2015) Annexin A1 counteracts chemokine-induced arterial myeloid cell recruitment. Circ Res 116:827-35
Liu, Mingyong; Chen, Keqiang; Yoshimura, Teizo et al. (2014) Formylpeptide receptors mediate rapid neutrophil mobilization to accelerate wound healing. PLoS One 9:e90613
Chen, Keqiang; Xiang, Yi; Huang, Jiaqiang et al. (2014) The formylpeptide receptor 2 (Fpr2) and its endogenous ligand cathelin-related antimicrobial peptide (CRAMP) promote dendritic cell maturation. J Biol Chem 289:17553-63
Arroyo, Daniela S; Soria, Javier A; Gaviglio, Emilia A et al. (2013) Toll-like receptor 2 ligands promote microglial cell death by inducing autophagy. FASEB J 27:299-312

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