Cytokine expression and signaling in drug-induced cellular senescence

Oncogene. 2010 Jan 14;29(2):273-84. doi: 10.1038/onc.2009.318. Epub 2009 Oct 5.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Bromodeoxyuridine / pharmacology*
  • Cell Line, Tumor
  • Cellular Senescence / drug effects*
  • Cytokines / genetics
  • Cytokines / metabolism*
  • Distamycins / pharmacology*
  • Drug Synergism
  • HeLa Cells
  • Humans
  • Interferons / genetics
  • Interferons / metabolism
  • Interleukin-10 / genetics
  • Interleukin-10 / metabolism
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Interleukin-8 / genetics
  • Interleukin-8 / metabolism
  • Interleukins / genetics
  • Interleukins / metabolism
  • Janus Kinase 1 / genetics
  • Janus Kinase 1 / metabolism
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction / drug effects*


  • Cytokines
  • Distamycins
  • Interleukin-6
  • Interleukin-8
  • Interleukins
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • interleukin-24
  • Interleukin-10
  • stallimycin
  • Interferons
  • Janus Kinase 1
  • Bromodeoxyuridine
  • interleukin 20