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Cytokine expression and signaling in drug-induced cellular senescence

Oncogene volume 29, pages 273–284 (2010)Cite this article

Abstract

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 γ (IFNγ), IFNβ 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 IFNβ–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.

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Acknowledgements

We thank Ondřej Horváth and Michal Koc for assistance, and Jan Frič and Ondřej Staněk for help with ELISA. This work was supported by the Grant Agency of the Academy of Sciences of the Czech Republic (Project IAA500390501), the Grant Agency of the Czech Republic (Project 204/08/1418), the European Commission (project TRIREME), Grant LC545 of the Ministry of Education, Youth and Sports of the Czech Republic, and the Institutional Grant (Project AV0Z5039906).

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Author notes

  1. Z Novakova

    Present address: 6Current address: Biology of Reproduction Department, Institute of Animal Science, Prague, Czech Republic.,

  2. L Janderova-Rossmeislova

    Present address: 7Current address: Department of Sports Medicine, 3rd Faculty of Medicine, Charles University, Prague, Czech Republic.,

  3. J Dobrovolna

    Present address: 8Current address: Department of Microbiology and Immunology, Hospital for Special Surgery, Weill Medical College of Cornell University, New York, NY, USA.,

  4. Z Horejsi

    Present address: 9Current address: DNA Damage Response Laboratory, Cancer Research UK, Clare Hall Laboratories, South Mims, UK.,

Authors and Affiliations

  1. Department of Genome Integrity, Institute of Molecular Genetics, v.v.i., Academy of Sciences of the Czech Republic, Prague, Czech Republic

    Z Novakova, S Hubackova, M Kosar, M Vancurova, J Bartek & Z Hodny

  2. Department of Biology of Cell Nucleus, Institute of Molecular Genetics, v.v.i., Academy of Sciences of the Czech Republic, Prague, Czech Republic

    Z Novakova, L Janderova-Rossmeislova, J Dobrovolna, P Hozak & Z Hodny

  3. Laboratory of Cell Reproduction, Institute of Microbiology, v.v.i., Academy of Sciences of the Czech Republic, Prague, Czech Republic

    P Vasicova

  4. Department of Molecular Virology, Institute of Molecular Genetics, v.v.i., Academy of Sciences of the Czech Republic, Prague, Czech Republic

    Z Horejsi

  5. Department of Cell Cycle and Cancer, and Centre for Genotoxic Stress Research, Institute of Cancer Biology, Danish Cancer Society, Copenhagen, Denmark

    J Bartek

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  1. Z Novakova
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Correspondence to J Bartek or Z Hodny.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Novakova, Z., Hubackova, S., Kosar, M. et al. Cytokine expression and signaling in drug-induced cellular senescence. Oncogene 29, 273–284 (2010). https://doi.org/10.1038/onc.2009.318

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