Acidic fibroblast growth factor (FGF-1) signaling inhibits peroxynitrite-induced cell death during pancreatic tumorigenesis.
Previous immunohistochemical studies have demonstrated enhanced appearance of FGF-1 and nitrotyrosine, a footprint of reactive nitrogen species peroxynitrite (ONOO(-)), in human pancreatic adenocarcinoma. We have examined the consequences of constitutive exposure to FGF-1 in nontumorigenic rat ductal epithelial cells (ARIP). ARIP cells were transduced with either a secreted chimera of FGF-1, ARIP(FGF-1), or a control plasmid, 65 RIP(betag). These cells were evaluated for alteration in growth and morphology, responses to ONOO(-) (protein tyrosine nitration/phosphorylation), and in vivo tumor formation. ARIP(FGF-1) cells, in contrast to 65 RIP(betag), demonstrated a transformed morphology, a 2-fold increased growth rate, and enhanced protein tyrosine phosphorylation. Treatment with 150 microM ONOO(-) resulted in 86 and 7% (p <.01) death of ARIP(betag) and ARIP(FGF-1), respectively. Exposure of 65 RIP(betag) cells to ONOO(-) enhanced tyrosine phosphorylation and tyrosine nitration of several polypeptides. Cell signaling by FGF-1 enhanced both phosphorylation and nitration of tyrosine residues in target proteins modified by ONOO(-). ARIP(betag) cells failed to exhibit tumor formation in nude mice, but at d 7 in vivo cells were TUNEL and nitrotyrosine positive and FGF-1 negative. ARIP(FGF-1) cells readily formed tumor nodules, exhibiting features of pancreatic adenocarcinoma and demonstrating FGF-1-positive, nitrotyrosine-positive, and TUNEL-negative epithelium. These results suggest an interdependent role between FGF-1 and ONOO(-) during the development and progression of pancreatic adenocarcinoma.
Vickers
S M
SM
Department of Surgery, The University of Alabama at Birmingham, Birmingham, AL 35294-0007, USA. smv@uab.edu
MacMillan-Crow
L
L
Huang
Z
Z
Thompson
J A
JA
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D016220:Fibroblast Growth Factor 1; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D009566:Nitrates / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D014161:Transduction, Genetic
D005609:Free Radicals; D009566:Nitrates; D012333:RNA, Messenger; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1; C039642:peroxynitric acid