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.
Novakova
Z
Z
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
Hubackova
S
S
Kosar
M
M
Janderova-Rossmeislova
L
L
Dobrovolna
J
J
Vasicova
P
P
Vancurova
M
M
Horejsi
Z
Z
Hozak
P
P
Bartek
J
J
Hodny
Z
Z
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