Cytokine expression and signaling in drug-induced cellular senescence

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 0 -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 c (IFNc), IFNb 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 IFNb-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.

Up-regulation of the interferon-related genes in BRCA2 knockout epithelial cells

“…Some reports attribute the expression of IFN-related genes to cellular senescence [39,40]. To investigate this possibility, we measured the activity of β-galactosidase, a senescence marker, in BRCA2 −/− and BRCA2 +/+ cells.…”

Resistance to discodermolide, a microtubule-stabilizing agent and senescence inducer, is 4E-BP1–dependent

“…Many stimuli can trigger senescence, including telomere shortening (replicative senescence), oncogene activation, and DNA damage. The cellular program executing senescence is dependent on DNA damage checkpoints and mitogenic signaling networks including STAT1, RAS, and PI3K (7)(8)(9). Senescence is considered a tumor-suppressive mechanism in many malignancies (10), and the appreciation that many chemotherapeutic agents induce senescence has prompted a resurgence of interest in prosenescent anti-cancer therapies.…”

Interleukin 6 Signaling Regulates Promyelocytic Leukemia Protein Gene Expression in Human Normal and Cancer Cells

“…Expression of PML is stimulated by interferons of type I and II (9 -12), which are produced during cellular responses to viral infection (for review, see Ref. 56) and some genotoxic insults (32,33). Response of PML to both types of interferons is mediated via transcription factors STAT1 and STAT2 (27), and it is suppressed by inhibitors of histone deacetylases (47).…”

“…5 As mentioned above, the common denominator of these two types of stresses (viral and genotoxic) is activation of a complex cytokine network including induction and secretion of IL6 (26, 32, 76 -78). In our previous work we showed that both JAK/STAT1/2 and JAK/ STAT3 signaling is involved in stress-induced PML gene transcription (32,33). One of the key questions raised by those studies was which other cytokines in addition to interferons induce PML (13).…”

“…29 -31), which can also include type I and type II interferons (32). Activated JAK/STAT signaling accompanying lasting DNA damage response during drug-induced premature senescence contributes to multiplication of nuclear PML compartment through modulation of PML transcript level (33).…”