Interferon receptor expression regulates the antiproliferative effects of interferons on cancer cells and solid tumors

Wagner, Tobias; Velichko, Sharlene; Chesney, Steven K.; Biroc, Sandra L.; Harde, Dean; Vogel, Dávid; Croze, Ed

doi:10.1002/ijc.20236

Cited by 70 publications

(52 citation statements)

References 54 publications

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“…Of course, for a drug against a disease such as cancer, an increased antiproliferative activity of IFN would be desired. Our data suggest that by further increasing the affinity of IFN for IFNAR1, such an increased activity could be achieved, even in cancer cells that have lost their responsiveness to IFNs by receptor down-regulation (49).…”

Section: Discussionmentioning

confidence: 81%

“…In Daudi cells, low concentrations of IFNs (pM) already cause growth arrest, which may be linked to higher levels of the interferon receptors on the surfaces of Daudi cells than on WISH cells (6). A recent report has suggested that tumor cells have a reduced level of interferon receptors, making them resistant to the antiproliferative activity of IFNs (49). Thus, it seems that interferon receptor concentrations affect the biological activities of IFNs.…”

Section: Discussionmentioning

confidence: 99%

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Inquiring into the Differential Action of Interferons (IFNs): an IFN-α2 Mutant with Enhanced Affinity to IFNAR1 Is Functionally Similar to IFN-β

Jaitin

Roisman

Jaks

et al. 2006

Molecular and Cellular Biology

206

243

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Alpha and beta interferons (IFN-␣Type I interferons (IFNs) form a family of multifunctional cytokines initially described for their direct antiviral effect but now also recognized as major elements of the immune response (19,46). Differential activities of IFN subtypes have been reported (3) and used in the clinic for the treatment of various pathologies, including viral hepatitis (IFN-␣2) and multiple sclerosis (IFN-␤) (32). All type I IFNs are recognized by a single shared receptor composed of two transmembrane proteins, IFNAR1 and IFNAR2. Because of the much faster k on and much slower k off of IFN-␣2 towards IFNAR2 than those measured for IFNAR1 (18,34,40), a two-step assembling mechanism was proposed for the interaction between IFN and the two receptors (Fig. 1B). After binding of IFN-␣2 to IFNAR2 (k a1 ), IFNAR1 transiently associates in a second step to the complex (k a2 ) (18,25). Owing to the short lifetime of the IFN-␣2-IFNAR1 interaction, the complex dissociates (k d2 ) and reassociates (k a2 ) in a fast manner. Thus, depending on the receptor surface concentrations and ligand binding affinities, only part of the bound ligand is involved in the active ternary complex.After formation of the ternary complex, the interferon signal is transduced through the receptor-associated JAK kinases, with the STAT transcription factors as their main targets (3).

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Inquiring into the Differential Action of Interferons (IFNs): an IFN-α2 Mutant with Enhanced Affinity to IFNAR1 Is Functionally Similar to IFN-β

Jaitin

Roisman

Jaks

et al. 2006

Molecular and Cellular Biology

206

243

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“…Sections were stained with hematoxylin-eosin (H&E) for histological analysis. The protocol closely followed that used successfully by Wagner et al (27).…”

Section: Determination Of Icmentioning

confidence: 98%

An Interferon α2 Mutant Optimized by Phage Display for IFNAR1 Binding Confers Specifically Enhanced Antitumor Activities

Kalie¹,

Jaitin²,

Abramovich

et al. 2007

Journal of Biological Chemistry

122

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All ␣-interferons (IFN␣) bind the IFNAR1 receptor subunit with low affinity. Increasing the binding affinity was shown to specifically increase the antiproliferative potency of IFN␣2. Here, we constructed a phage display library by randomizing three positions on IFN␣2 previously shown to confer weak binding to IFNAR1. The tightest binding variant selected, comprised of mutations H57Y, E58N, and Q61S (YNS), was shown to bind IFNAR1 60-fold tighter compared with wild-type IFN␣2, and 3-fold tighter compared with IFN␤. Binding of YNS to IFNAR2 was comparable with wild-type IFN␣2. The YNS mutant conferred a 150-fold higher antiproliferative potency in WISH cells compared with wild-type IFN␣2, whereas its antiviral activity was increased by only 3.5-fold. The high antiproliferative activity was related to an induction of apoptosis, as demonstrated by annexin V binding assays, and to specific gene induction, particularly TRAIL. To determine the potency of the YNS mutant in a xenograft cancer model, we injected it twice a week to nude mice carrying transplanted MDA231 human breast cancer cells. After 5 weeks, no tumors remained in mice treated with YNS, whereas most mice treated with wild-type IFN␣2 showed visible tumors. Histological analysis of these tumors showed a significant antiangiogenic effect of YNS, compared with wild-type IFN␣2. This work demonstrates the application of detailed biophysical understanding in the process of protein engineering, yielding an interferon variant with highly increased biological potency. Type I interferons (IFNs)3 are multifunctional cytokines that orchestrate the antiviral innate immunity in vertebrates, acting in virtually every nucleated cell. They belong to the helical cytokine superfamily (1), and consist of at least 17 different members in humans: 13 different IFN␣ subtypes, IFN␤, IFN, and IFN, all of which share significant amino acid homology (2).All type I interferons induce their biological effects through a common receptor, composed of two distinct transmembrane proteins, namely IFNAR1 and IFNAR2 (3-5). Upon formation of the ternary complex, the interferon signal is transduced through receptor-associated Janus family kinases (JAK), which activate the signal transducers and activators of transcription (STAT) proteins. These, in turn, form homo-and heterodimers that translocate to the nucleus, where they directly regulate the transcription of specific interferon responsive genes (6).In addition to their important roles at the first line of defense against viral infections (7) and in modulation of the adaptive immune system (8), type I interferons are capable of inducing a significant antiproliferative activity (9). Consequently, interferons are widely used in the clinic for the treatment of multiple sclerosis and chronic hepatitis (10, 11), as well as for a number of malignancies (12). However, the efficiency of interferon treatment in the majority of cancers is modest, limited by side effects and varying resistance of malignant cells to this treatment (13,14).Despite their...

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“…It was shown that a decrease in cell surface concentration of one or both of the receptor subunits reduces cell sensitivity and alters signaling (5,25,26,43,49). In addition, a clear correlation between the efficiency of interferon as an antiviral drug or a cancer drug and surface receptor concentration was suggested (7,12,27,49). Using stably transfected cells, it was shown that an increased number of receptors resulted in an overall elevated sensitivity for IFNs, accompanied by a de-crease in interferon differential activity between the low-and high-affinity cytokines IFN-␣ and -␤ (29).…”

mentioning

confidence: 99%

Stochastic Receptor Expression Determines Cell Fate upon Interferon Treatment

Levin

Harari

Schreiber

2011

Molecular and Cellular Biology

116

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Type I interferons trigger diverse biological effects by binding a common receptor, composed of IFNAR1 and IFNAR2. Intriguingly, while the activation of an antiviral state is common to all cells, antiproliferative activity and apoptosis affect only part of the population, even when cells are stimulated with saturating interferon concentrations. Manipulating receptor expression by different small interfering RNA (siRNA) concentrations reduced the fraction of responsive cells independent of the interferon used, including a newly generated, extremely tight-binding variant. Reduced receptor numbers increased 50% effective concentrations (EC 50 s) for alpha interferon 2 (IFN-␣2) but not for the tight-binding variant. A correlation between receptor numbers, STAT activation, and gene induction is observed. Our data suggest that for a given cell, the response is binary (؉/؊) and dependent on the stochastic expression levels of the receptors on an individual cell. A low number of receptors suffices for antiviral response and is thus a robust feature common to all cells. Conversely, a high number of receptors is required for antiproliferative activity, which allows for fine-tuning on a single-cell level.Type I interferons (IFNs) form a class of cytokines capable of mediating antiviral, growth inhibitory, and immunoregulatory activities (10,36,46). Consisting of 18 members in humans (32), all IFNs induce their biological activities through binding to the same receptor complex, composed of the two transmembrane proteins IFNAR1 and IFNAR2 (1). Upon formation of the ternary complex, the interferon signal is transduced through receptor-associated Janus kinases (JAK), which activate the signal transducers and activators of transcription (STAT) proteins. These, in turn, form homo-and heterodimers that translocate to the nucleus to promote the expression of interferon-stimulated genes (ISGs) (45).Despite their common biological activities and sequence homologies, type I IFNs are not redundant but rather induce their activities differentially (9, 41). These differences take effect in various ways, most notably in the antiviral (AV) and antiproliferative (AP) potencies of interferon subtypes (16,33) and in their abilities to induce different gene expression patterns (11,14,38,48). The AP activities of IFNs are a result of both apoptosis and cell cycle arrest (17,20,40). A profound example for differential activity is the substantially higher AP response induced by beta interferon (IFN-␤) than by 14,21,41). However, it should be noted that most of the differences between IFN-␣2 and IFN-␤ are quantitative and not qualitative; thus, higher IFN-␣2 concentrations mimic most IFN-␤ activities.IFNAR1 and IFNAR2 receptor subunits make distinct contributions to interferon binding, as IFNAR1 binds IFN-␣ with micromolar affinities, while the IFNAR2 subunit binds at nanomolar affinities (6). Nevertheless, the activation of both receptors is necessary to induce the interferon signal (3, 23).Mutagenesis studies have shown that the binding sites f...

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Interferon receptor expression regulates the antiproliferative effects of interferons on cancer cells and solid tumors

Cited by 70 publications

References 54 publications

Inquiring into the Differential Action of Interferons (IFNs): an IFN-α2 Mutant with Enhanced Affinity to IFNAR1 Is Functionally Similar to IFN-β

Inquiring into the Differential Action of Interferons (IFNs): an IFN-α2 Mutant with Enhanced Affinity to IFNAR1 Is Functionally Similar to IFN-β

An Interferon α2 Mutant Optimized by Phage Display for IFNAR1 Binding Confers Specifically Enhanced Antitumor Activities

Stochastic Receptor Expression Determines Cell Fate upon Interferon Treatment

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