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.
- MeSH
- bromodeoxyuridin farmakologie MeSH
- cytokiny genetika metabolismus MeSH
- distamyciny farmakologie MeSH
- HeLa buňky MeSH
- interferony genetika metabolismus MeSH
- interleukin-10 genetika metabolismus MeSH
- interleukin-6 genetika metabolismus MeSH
- interleukin-8 genetika metabolismus MeSH
- interleukiny genetika metabolismus MeSH
- Janus kinasa 1 genetika metabolismus MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- RNA interference MeSH
- signální transdukce účinky léků MeSH
- stárnutí buněk účinky léků MeSH
- synergismus léků MeSH
- transkripční faktor STAT1 genetika metabolismus MeSH
- western blotting MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- MeSH
- chromozomální aberace diagnóza MeSH
- distamyciny diagnostické užití MeSH
- fenotyp MeSH
- finanční podpora výzkumu jako téma MeSH
- hodnocení rizik MeSH
- karyotypizace metody normy trendy MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
