Abstract
Type I Interferon (IFN) and all-trans retinoic acid (RA) inhibit cell proliferation of squamous carcinoma cell lines (SCC). Examinations of growth-affected cell populations show that SCC lines ME-180 and SiHa treated with IFN-beta undergo a specific slower progression through the S phase that seems to trigger cellular death. In combination treatment RA potentiates IFN-beta effect in SCC ME-180 but not in SiHa cell line, partially resistant to RA antiproliferative action. RA added as single agent affects cell proliferation differently by inducing a slight G1 accumulation. The IFN-beta-induced S phase lengthening parallels the increased expression of PML, a nuclear phosphoprotein specifically up-regulated at transcriptional level by IFN, whose overexpression induces cell growth inhibition and tumor suppression. We report that PML up-regulation may account for the alteration of cell cycle progression induced by IFN-beta in SCC by infecting cells with PML-PINCO recombinant retrovirus carrying the PML-3 cDNA under the control of the 5' LTR. In fact PML overexpression reproduces the IFN-beta-induced S phase lengthening. These findings provide important insight into the mechanism of tumor suppressing function of PML and could allow PML to be included in the pathways responsible for IFN-induced cell growth suppression.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / pharmacology*
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Carcinoma, Squamous Cell / drug therapy
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Carcinoma, Squamous Cell / metabolism
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Carcinoma, Squamous Cell / pathology*
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Cell Division / drug effects
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DNA, Neoplasm / biosynthesis
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Female
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Gene Expression Regulation, Neoplastic / drug effects
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Growth Inhibitors / administration & dosage
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Growth Inhibitors / pharmacology
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Humans
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Interferon Type I / administration & dosage
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Interferon Type I / pharmacology*
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Neoplasm Proteins / biosynthesis*
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Neoplasm Proteins / genetics
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Nuclear Proteins*
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Promyelocytic Leukemia Protein
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Protein Isoforms / biosynthesis
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Protein Isoforms / genetics
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Recombinant Proteins
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S Phase / drug effects*
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Transcription Factors / biosynthesis*
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Transcription Factors / genetics
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Tretinoin / administration & dosage
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Tretinoin / pharmacology
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Tumor Cells, Cultured
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Tumor Suppressor Proteins
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Up-Regulation / drug effects
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Uterine Cervical Neoplasms / drug therapy
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Uterine Cervical Neoplasms / metabolism
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Uterine Cervical Neoplasms / pathology*
Substances
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Antineoplastic Agents
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DNA, Neoplasm
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Growth Inhibitors
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Interferon Type I
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Neoplasm Proteins
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Nuclear Proteins
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Promyelocytic Leukemia Protein
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Protein Isoforms
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Recombinant Proteins
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Transcription Factors
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Tumor Suppressor Proteins
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PML protein, human
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Tretinoin