Cytotoxic response of ovarian cancer cell lines to IFN-gamma is associated with sustained induction of IRF-1 and p21 mRNA.
Interferon-gamma (IFN-gamma) has some anti-tumour activity in human ovarian cancer. This cytokine inhibited proliferation in three of four ovarian cancer cell lines in vitro. We then compared the action of IFN-gamma in two cell lines, one sensitive and one resistant to its growth inhibitory effects. IFN-gamma signalling appeared normal in both cell lines, with stat1 DNA binding activity detectable at 30 min. Continuous exposure to IFN-gamma for 2-3 days was necessary for an irreversible effect on cell growth and apoptosis in cells sensitive to growth inhibition. During this time there was an increase in mRNA for the CKI p21, but no alterations in mRNA levels for other members of the CKI family. Maintenance of p21 mRNA required continuous mRNA synthesis. mRNA for the transcription factor IRF-1 was also induced in growth inhibited cells with similar kinetics to those observed for p21. Maximal induction of both p21 and IRF-1 mRNA was observed after 2-3 days IFN-gamma exposure as the cells became committed to cell death. There was also a rapid increase in p21 and IRF-1 mRNA in cells resistant to the growth inhibitory effects of IFN-gamma, but this increase was not maintained. Thus, continuous interaction with the IFN-gamma receptor, together with a sustained induction of p21 and IRF-1, is associated with growth inhibitory and apoptotic effects of IFN-gamma in ovarian cancer cells.
Burke
F
F
Biological Therapies Laboratory, Imperial Cancer Research Fund, London, UK.
Smith
P D
PD
Crompton
M R
MR
Upton
C
C
Balkwill
F R
FR
D000230:Adenocarcinoma / Q000188:drug therapy / Q000276:immunology*; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D050856:Interferon Regulatory Factor-1; D016898:Interferon-alpha / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000276:immunology*; D010750:Phosphoproteins / Q000096:biosynthesis* / Q000187:drug effects; D016283:Proto-Oncogene Proteins p21(ras) / Q000096:biosynthesis* / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D017471:Receptors, Interferon / Q000187:drug effects / Q000502:physiology; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D016898:Interferon-alpha; D010750:Phosphoproteins; D012333:RNA, Messenger; D017471:Receptors, Interferon; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)