Interferon Receptor Signaling in Malignancy: A Network of Cellular Pathways Defining Biological Outcomes

Abstract

Interferons (IFNs) are cytokines with important anti-proliferative activity and exhibit key roles in immune surveillance against malignancies. Early work initiated over 3 decades ago led to the discovery of IFN receptor activated Jak-Stat pathways and provided important insights into mechanisms for transcriptional activation of interferon stimulated genes (ISGs) that mediate IFN-biological responses. Since then, additional evidence has established critical roles for other receptor activated signaling pathways in the induction of IFN-activities. These include MAPK pathways, mTOR cascades and PKC pathways. In addition, specific microRNAs (miRNAs) appear to play a significant role in the regulation of IFN-signaling responses. This review focuses on the emerging evidence for a model in which IFNs share signaling elements and pathways with growth factors and tumorigenic signals, but engage them in a distinctive manner to mediate anti-proliferative and antiviral responses.

Intersection of mTOR and STAT signaling in immunity

“…There has been extensive evidence that STAT signaling pathways play key and essential roles in the generation of Type I IFN responses [57–59]. Recent studies have also provided evidence that mTORC2 activity is required for transcriptional regulation of IFN-stimulated genes (ISGs) [18,60].…”

“…4). An implication of this model is that competition for specific use of mTOR pathways between IFNs and oncogenic signals/growth factors may impact signaling specificity and differential biological outcomes [59] (Fig. 4).…”

Human Schlafen 5 (SLFN5) Is a Regulator of Motility and Invasiveness of Renal Cell Carcinoma Cells

“…nterferons (IFNs) are cytokines with important antineoplastic activities and therefore are frequently utilized in the treatment of cancer (1)(2)(3)(4). A malignancy that exhibits sensitivity to interferon treatment is renal cell carcinoma (RCC) (5).…”

“…Prior evidence has implicated members of the Schlafen family in the regulation of tumorigenesis (13)(14)(15)(16)(17)(18). Notably, expression of various members of this family is upregulated following treatment with type I IFNs (17)(18)(19), cytokines known to promote induction of antineoplastic, antiviral, and immunoregulatory effects (1)(2)(3)(4). Despite the induction of human and mouse SLFN genes by IFNs, the precise mechanisms by which SLFNs mediate antineoplastic responses in different types of malignant human cells remain to be determined.…”

No Love Lost Between Viruses and Interferons

“…Further diversification of the sets of ISGs induced by type I IFNs occurs via heterodimerization of STAT1 with IRF-1 or subunits of NF-κB, as well as by activation of other STAT family members (STAT3-6), the availability of the latter being cell type dependent (77); all of those complexes can bind to promoters of additional genes that are otherwise not induced by ISGF3. Furthermore, various MAPK pathways are stimulated by type I IFNs, also contributing to the spectrum of induced genes (78). Apart from that, IFN-β can induce several genes that are not inducible by other type I IFNs, such as IFN-α2.…”