Acidic fibroblast growth factor (FGF-1) signaling inhibits peroxynitrite-induced cell death during pancreatic tumorigenesis.

Abstract

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.

• Authors: S M Vickers, L MacMillan-Crow, Z Huang, J A Thompson
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 30 Issue 9 Pg. 957-66 (May 01 2001) ISSN: 0891-5849 [Print] United States
• PMID: 11316575 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Free Radicals
• Nitrates
• RNA, Messenger
• Fibroblast Growth Factor 2
• Fibroblast Growth Factor 1
• peroxynitric acid

Topics

• Animals
• Cell Death (drug effects)
• Cell Line
• Fibroblast Growth Factor 1
• Fibroblast Growth Factor 2 (genetics, pharmacology, physiology)
• Free Radicals (metabolism)
• Humans
• Nitrates (pharmacology)
• Pancreatic Neoplasms (etiology, pathology, physiopathology)
• RNA, Messenger (genetics, metabolism)
• Rats
• Signal Transduction
• Transduction, Genetic