Abstract
Pancreatic cancer is the most aggressive malignant disease, ranking as the fourth leading cause of cancer-related death among men and women in the United States. Interferon alpha (IFNα) has been used to treat pancreatic cancer, but its clinical application has been significantly hindered due to the low antitumor activity. We used a “cDNA in-frame fragment library” screening approach to identify short peptides that potentiate the antitumor activity of interferons. A short positively charged peptide derived from the C-terminus of placental growth factor-2 (PLGF-2) was selected to enhance the activity of IFNα. For this, we constructed a synthetic interferon hybrid molecule (SIFα) by fusing the positively charged PLGF-2 peptide to the C-terminus of the human IFNα. Using human pancreatic cell lines (ASPC and CFPAC1) as a model system, we found that SIFα exhibited a significantly higher activity than did the wild-type IFNα in inhibiting the tumor cell growth. The enhanced activity of the synthetic SIFα was associated with the activation of interferon pathway target genes and the increased binding of cell membrane receptor. This study demonstrates the potential of a synthetic SIFα as a novel antitumor agent.
Highlights
Fused “in frame” to the C-terminus of IFN
Among the identified IFN enhancer peptides (IEP), three contained a consensus amino acid sequence consisting of poly-arginine/lysine positively charged residues. We found that this consensus IFN-enhancer peptides (IEPs) was related to the C-terminus of placental growth factor-2 (PLGF-2) protein (Fig. S1)
A peptide containing this IEP is known to enhance the function of vascular endothelial growth factor-A, platelet-derived growth factor-BB, and bone morphogenetic protein-211
Summary
Fused “in frame” to the C-terminus of IFN. By screening, we identified short cDNA fragments that enhance the activity of IFN (“IFN enhancer peptide”, IEP). Three IEP peptides contain a short stretch of positively charged amino acids derived from placental growth factor-2 (PLGF-2)(Guo et al unpublished data). This short peptide has been shown to enhance the activity of three growth factors (vascular endothelial growth factor-A, platelet-derived growth factor-BB, and bone morphogenetic protein-2)[11]. In this proof-of-concept study, we examined whether this novel IEP peptide was able to potentiate the antitumor activity of IFNα. We examined whether the synthetic interferon was able to modulate the effect of the chemotherapeutic drug gemcitabin (GEM) in human pancreatic cell lines
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