Cytokine expression and signaling in drug-induced cellular senescence.
Cellular senescence guards against cancer and modulates aging; however, the underlying mechanisms remain poorly understood. Here, we show that genotoxic drugs capable of inducing premature senescence in normal and cancer cells, such as 5-bromo-2'-deoxyuridine (BrdU), distamycin A (DMA), aphidicolin and hydroxyurea, persistently activate Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling and expression of interferon-stimulated genes (ISGs), such as MX1, OAS, ISG15, STAT1, PML, IRF1 and IRF7, in several human cancer cell lines. JAK1/STAT-activating ligands, interleukin 10 (IL10), IL20, IL24, interferon gamma (IFNgamma), IFNbeta and IL6, were also expressed by senescent cells, supporting autocrine/paracrine activation of JAK1/STAT. Furthermore, cytokine genes, including proinflammatory IL1, tumor necrosis factor and transforming growth factor families, were highly expressed. The strongest inducer of JAK/STAT signaling, cytokine production and senescence was BrdU combined with DMA. RNA interference-mediated knockdown of JAK1 abolished expression of ISGs, but not DNA damage signaling or senescence. Thus, although DNA damage signaling, p53 and RB activation, and the cytokine/chemokine secretory phenotype are apparently shared by all types of senescence, our data reveal so far unprecedented activation of the IFNbeta-STAT1-ISGs axis, and indicate a less prominent causative role of IL6-JAK/STAT signaling in genotoxic drug-induced senescence compared with reports on oncogene-induced or replicative senescence. These results highlight shared and unique features of drug-induced cellular senescence, and implicate induction of cancer secretory phenotype in chemotherapy.
Department of Genome Integrity, Institute of Molecular Genetics, v.v.i., Academy of Sciences of the Czech Republic, Prague, Czech Republic. hodny@img.cas.cz
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Novakova
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Hubackova
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Kosar
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Janderova-Rossmeislova
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Dobrovolna
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Vasicova
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Vancurova
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Horejsi
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Hozak
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Bartek
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Hodny
D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004214:Distamycins / Q000494:pharmacology*; D004357:Drug Synergism; D006367:HeLa Cells; D006801:Humans; D007372:Interferons / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000099180:Interleukin-24
D001973:Bromodeoxyuridine; D016207:Cytokines; D004214:Distamycins; D007372:Interferons; D016753:Interleukin-10; D015850:Interleukin-6; D016209:Interleukin-8; D007378:Interleukins; D053613:Janus Kinase 1; D050794:STAT1 Transcription Factor; D000099180:Interleukin-24; C494079:STAT1 protein, human; C030000:stallimycin; C422042:interleukin 20