title: Pegylated IFN-α sensitizes melanoma cells to chemotherapy and causes premature senescence in endothelial cells by IRF-1 mediated signaling.
abstract: Pegylated Interferon-α2b (pIFN-α) is an integral part of the drug regimen currently employed against melanoma. Interferon Regulatory Factor-1 (IRF-1) plays an important role in the transcriptional regulation of the IFN response, cell cycle and apoptosis. We have studied pIFN-α induced responses when combined with the chemotherapy agent, vinblastine in tumor and endothelial cell lines and the connection to IRF-1 signaling. Levels of IRF-1/IRF-2 protein expression were found to be decreased in tumor versus normal tissues. pIFN-α induced IRF-1 signaling in human melanoma (M14) and endothelial (EA.hy926) cells and enhanced cell death when combined with vinblastine. Upon combined IFN-α and vinblastine treatment, p21 expression, PARP cleavage and activated Bak levels were increased in M14 cells. An increase in p21 and cyclin D1 expression occurred in EA.hy926 cells after 6 h of treatment with pIFN-α which dissipated by 24 h. This biphasic response, characteristic of cellular senescence, was more pronounced upon combined treatment. Exposure of the EA.hy926 cells to pIFN-α was associated with an enlarged, multinucleated, β-galactosidase-positive senescent phenotype. The overall therapeutic mechanism of IFN-α combined with chemotherapy may be due to both direct tumor cell death via IRF-1 signaling and by premature senescence of endothelial cells and subsequent effects on angiogenesis in the tumor microenvironment.
authors.affiliation: Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: M
authors.initials: M
authors.lastname: Upreti
authors.forename: N A
authors.initials: NA
authors.lastname: Koonce
authors.forename: L
authors.initials: L
authors.lastname: Hennings
authors.forename: T C
authors.initials: TC
authors.lastname: Chambers
authors.forename: R J
authors.initials: RJ
authors.lastname: Griffin
mesh_terms: D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D050836:Interferon Regulatory Factor-2 / Q000378:metabolism*; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology / Q000627:therapeutic use*; D008545:Melanoma / Q000188:drug therapy*; D010641:Phenotype; D011092:Polyethylene Glycols / Q000494:pharmacology / Q000627:therapeutic use*; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000187:drug effects; D014747:Vinblastine / Q000494:pharmacology
chemical_list: D050856:Interferon Regulatory Factor-1; D050836:Interferon Regulatory Factor-2; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D014747:Vinblastine; C417083:peginterferon alfa-2b