Ad-IRF-1 induces apoptosis in esophageal adenocarcinoma.
The nuclear transcription factor interferon regulatory factor-1 (IRF-1) is a putative tumor suppressor, but the expression and function of IRF-1 in esophageal adenocarcinoma (EA) remain unknown. We hypothesized that IRF-1 expression was reduced or lost in EA and that restoration of IRF-1 would result in the apoptosis of EA cells in vitro and the inhibition of tumor growth in vivo. Three EA cell lines were used to examine IRF-1 expression, IFN-gamma responsiveness, and the effects of IRF-1 overexpression using a recombinant adenoviral vector (Ad-IRF-1). All three EA cell lines produced IRF-1 protein following IFN-gamma stimulation, although IFN-gamma did not induce cell death. In contrast, Ad-IRF-1 infection resulted in high levels of IRF-1 protein and triggered apoptosis in all three EA cell lines. Potential mechanisms for the differential response to IFN-gamma versus Ad-IRF-1--such as modulation of c-Met or extracellular regulated kinase signaling, or altered expression of IRF-2, Fas, or survivin--were investigated, but none of these mechanisms can account for this observation. In vivo administration of IRF-1 in a murine model of EA modestly inhibited tumor growth, but did not lead to tumor regression. Strategies aimed at increasing or restoring IRF-1 expression may have therapeutic benefits in EA.
Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
Gregory A
GA
Watson
Pierre E
PE
Queiroz de Oliveira
Michael T
MT
Stang
Michaele J
MJ
Armstrong
William E
WE
Gooding
Shih-Fan
SF
Kuan
John H
JH
Yim
Steven J
SJ
Hughes
D000230:Adenocarcinoma / Q000235:genetics*; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002469:Cell Separation; D004195:Disease Models, Animal; D004938:Esophageal Neoplasms / Q000235:genetics*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000235:genetics*; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000378:metabolism
D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma; D048049:Extracellular Signal-Regulated MAP Kinases