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
- Bromodeoxyuridine pharmacology MeSH
- Cytokines genetics metabolism MeSH
- Distamycins pharmacology MeSH
- HeLa Cells MeSH
- Interferons genetics metabolism MeSH
- Interleukin-10 genetics metabolism MeSH
- Interleukin-6 genetics metabolism MeSH
- Interleukin-8 genetics metabolism MeSH
- Interleukins genetics metabolism MeSH
- Janus Kinase 1 genetics metabolism MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Reverse Transcriptase Polymerase Chain Reaction MeSH
- RNA Interference MeSH
- Signal Transduction drug effects MeSH
- Cellular Senescence drug effects MeSH
- Drug Synergism MeSH
- STAT1 Transcription Factor genetics metabolism MeSH
- Blotting, Western MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Publication type
- Meeting Abstract MeSH
- MeSH
- Antineoplastic Agents immunology toxicity MeSH
- Immunity, Cellular radiation effects MeSH
- Antibody-Producing Cells drug effects MeSH
- Phagocytosis radiation effects MeSH
- Drug Evaluation MeSH
- Mice MeSH
- Platinum analogs & derivatives immunology toxicity MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- MeSH
- Antiviral Agents immunology MeSH
- Biological Assay MeSH
- Drug Evaluation MeSH
- Mice MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
