Inhibition of autocrine fibroblast growth factor signaling by the adenovirus-mediated expression of an antisense transgene or a dominant negative receptor in human glioma cells in vitro.
Autocrine fibroblast growth factor (FGF) signaling was genetically manipulated in human gliomas by an adenovirus-mediated strategy. Antisense inhibition of endogenous basic FGF (bFGF) expression showed inhibition of the proliferation of human glioma cells (U251MG, NMC-G1) without promoting apoptosis. The reduction in proliferation in response to antisense inhibition was reversed with an additional supplement of exogenous bFGF. On the other hand, the overexpression of a kinase defective mutant of the type I FGF receptor (dominant negative FGF receptor) resulted in not only growth inhibition but also marked apoptosis in U251MG cells. In the cells expressing a dominant negative FGF receptor, the reduction in cell number was not reversed by the exogenous bFGF supplement. Our data further implicated the significance of an autocrine FGF signaling loop in human gliomas. Cell survival activity may largely depend on the receptor-mediated pathway, which should be considered in the development of the molecular based therapeutics.
Aoki
Takachika
T
Department of Neurosurgery, Kurume University, School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan.
Kato
Seiya
S
Fox
Jonathan C
JC
Okamoto
Kenichi
K
Sakata
Kiyohito
K
Morimatsu
Minoru
M
Shigemori
Minoru
M
D000260:Adenoviruses, Human / Q000235:genetics; D000818:Animals; D001254:Astrocytoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D002455:Cell Division / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D005910:Glioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D006801:Humans; D016372:RNA, Antisense / Q000235:genetics* / Q000494:pharmacology; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D019076:Transgenes; D014407:Tumor Cells, Cultured
D016372:RNA, Antisense; D017468:Receptors, Fibroblast Growth Factor; D016222:Fibroblast Growth Factor 2; C496348:FGFR1 protein, human; C496350:Fgfr1 protein, rat; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1