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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Cell Cycle Checkpoints / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects*
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Cell Proliferation / genetics
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Deoxycytidine / analogs & derivatives
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Deoxycytidine / pharmacology
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Gemcitabine
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Gene Expression Regulation, Neoplastic / drug effects
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HEK293 Cells
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Humans
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Interferon-alpha / chemistry
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Interferon-alpha / genetics
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Interferon-alpha / pharmacology*
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Models, Molecular
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Pancreatic Neoplasms / genetics
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Pancreatic Neoplasms / metabolism
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Pancreatic Neoplasms / pathology
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Peptides / chemistry
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Peptides / genetics
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Peptides / pharmacology*
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Placenta Growth Factor
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Pregnancy Proteins / chemistry
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Pregnancy Proteins / genetics
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Protein Conformation
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / pharmacology*
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Reverse Transcriptase Polymerase Chain Reaction
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STAT1 Transcription Factor / genetics
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STAT1 Transcription Factor / metabolism
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Signal Transduction / drug effects
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Signal Transduction / genetics
Substances
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Antineoplastic Agents
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Interferon-alpha
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PGF protein, human
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Peptides
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Pregnancy Proteins
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Recombinant Fusion Proteins
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STAT1 Transcription Factor
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Deoxycytidine
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Placenta Growth Factor
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Gemcitabine