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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010015-17
Application #
8552635
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
17
Fiscal Year
2012
Total Cost
$489,899
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
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