The
G protein-coupled formylpeptide receptor (FPR), known to mediate phagocytic leucocyte chemotaxis in response to bacterial- and host-derived agonists, was expressed by
tumor cells in specimens of surgically removed more highly malignant human
gliomas. In human
glioblastoma cell lines, FPR activation increased cell motility, tumorigenicity and production of angiogenic factors. In studies of the mechanistic basis for the selective expression of FPR in more highly
malignant gliomas, we found that the
DNA methyltransferase inhibitor
5-Aza-2'-deoxycytidine (Aza), while promoting the differentiation of human
glioblastoma cells, downregulated FPR expression. Aza also reduced the global methylation levels in
glioblastoma cells and activated the pathway of p53
tumor suppressor. Methylation-specific polymerase chain reaction revealed that Aza treatment of
tumor cells reduced the methylation of p53 promoter, which was accompanied by increased expression of p53 gene and
protein. In addition, overexpression of p53 in
glioblastoma cells mimicked the effect of Aza treatment as shown by increased cell differentiation but reduction in FPR expression, the capacity of
tumor sphere formation in soft
agar and
tumorigenesis in nude mice. Furthermore, Aza treatment or overexpression of the wild-type p53 in
glioblastoma cells increased the binding of p53 to FPR promoter region shown by
chromatin immunoprecipitation. These results indicate that increased methylation of p53 gene retains human
glioblastoma cells at a more poorly differentiated phase associated with the aberrant expression of FPR as a
tumor-promoting
cell surface receptor.