Gastrin-releasing peptide receptors regulate proliferation of C6 Glioma cells through a phosphatidylinositol 3-kinase-dependent mechanism.
Gastrin-releasing peptide (GRP) has been proposed as a major growth factor in brain tumors, and GRP receptor (GRPR) antagonists show antiproliferative effects in experimental gliomas. However, the underlying molecular events downstream of GRPR activation remain poorly understood. In the present study, we examined the role of the GRPR in regulating proliferation of glioma cells in vitro and its possible interaction with the phosphatidylinositol 3-kinase (PI3K) signaling pathway. Expression of GRPR mRNA and protein in C6, U-87MG, and U-373MG glioma cells was analyzed by reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. Proliferation of C6 and U-87MG, but not U-373MG cells was significantly inhibited by the GRPR antagonist RC-3095, whereas the GRPR agonist bombesin (BB) significantly enhanced proliferation of C6 cells. The BB-induced stimulatory effect on cell proliferation was prevented by either RC-3095 or the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. Our results provide the first evidence that the GRPR regulates proliferation of C6 glioma cells and suggest that PI3K is required for GRPR-mediated stimulation of glioma growth.
Flores
Debora Gazzana
DG
Cancer Research Laboratory, Academic Hospital Research Center, Federal University of Rio Grande do Sul, Rua Ramiro Barcelos, 2350, 90035-003 Porto Alegre, RS, Brazil.
de Farias
Caroline Brunetto
CB
Leites
Juliano
J
de Oliveira
Marianne Schrader
MS
Lima
Rodrigo Cruz
RC
Tamajusuku
Alessandra Sayuri Kikuchi
AS
Di Leone
Luciane Pons
LP
Meurer
Luise
L
Brunetto
Algemir Lunardi
AL
Schwartsmann
Gilberto
G
Lenz
Guido
G
Roesler
Rafael
R
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001839:Bombesin / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005910:Glioma / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051381:Rats; D018004:Receptors, Bombesin / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D010446:Peptide Fragments; D018004:Receptors, Bombesin; C071363:bombesin (6-14), Tpi(6)-Leu(13)-psi(CH2NH)-Leu(14)-; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D001839:Bombesin