Cytokine-induced senescence in tumors is based on sustained activation of STAT1- and NFκB-dependent gene regulatory signatures

Senescence is a tripartite cellular phenotype characterized by permanent growth arrest, resistance to apoptosis, and high secretory activity. Besides its physiological role in embryonic development and pathophysiological contribution to age-related tissue degeneration, in the context of tumor development senescence is an important suppressor mechanism, that counteracts accelerated proliferation. Among the many stressors that induce senescence is the external stimulation by cytokines. Although cytokine-induced senescence (CIS) has repeatedly been reported in the literature, the signaling networks leading to the senescent phenotype remained enigmatic. Here, we used two models of tumor-associated (TA)-CIS: (i) in vitro treatment of human A204 cancer cells with interferon (IFN)-γ and tumor necrosis factor (TNF) and (ii) in vivo senescence induction by adoptive transfer of T helper 1 (T_H1) cells into tumor-bearing RIP-Tag2 mice. In both models, gene expression profiling and signal transduction analysis highlighted the persistent activation of IFN-receptor/STAT1 and TNF-receptor/NF-κB/p38 signaling leading to downregulation of cell cycle genes, upregulation of secretory factors and, remarkably, upregulation of pro-apoptotic as well as anti-apoptotic genes. Protein analysis further demonstrated that the growth-arrested tumor cells were not subject to apoptotic death. Altogether, we define a cross-species TA-CIS core gene and signal transduction signature that may be exploited for therapeutic ends for cancer.