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Abstract
The 26S proteasome is a negative regulator of type I interferon (IFN-α/β) signaling. Inhibition of the 26S proteasome by small molecules may be a new strategy to enhance the efficacy of type I IFNs and reduce their side effects. Using cell-based screening assay for new 26S proteasome inhibitors, we found that emodin, a natural anthraquinone, was a potent inhibitor of the human 26S proteasome. Emodin preferably inhibited the caspase-like and chymotrypsin-like activities of the human 26S proteasome and increased the ubiquitination of endogenous proteins in cells. Computational modeling showed that emodin exhibited an orientation/conformation favorable to nucleophilic attack in the active pocket of the β1, β2, and β5 subunits of the 26S proteasome. Emodin increased phosphorylation of STAT1, decreased phosphorylation of STAT3 and increased endogenous gene expression stimulated by IFN-α. Emodin inhibited IFN-α-stimulated ubiquitination and degradation of type I interferon receptor 1 (IFNAR1). Emodin also sensitized the antiproliferative effect of IFN-α in HeLa cervical carcinoma cells and reduced tumor growth in Huh7 hepatocellular carcinoma-bearing mice. These results suggest that emodin potentiates the antiproliferative effect of IFN-α by activation of JAK/STAT pathway signaling through inhibition of 26S proteasome-stimulated IFNAR1 degradation. Therefore, emodin warrants further investigation as a new means to enhance the efficacy of IFN-α/β.
Highlights
Type I interferons (IFN-α and IFN-β) play central roles in the innate immune response and exhibit antiviral, antiproliferative, and immunomodulatory effects by activation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway signaling [1]
These results suggest that emodin potentiates the antiproliferative effect of IFN-` by activation of JAK/STAT pathway signaling through inhibition of 26S proteasome-stimulated IFNAR1 degradation
The activity of luciferase-cODC was increased when the cells were treated with the 26S proteasome inhibitor bortezomib (Figure 1B), indicating that luciferase-cODC was degraded by the 26S proteasome
Summary
Type I interferons (IFN-α and IFN-β) play central roles in the innate immune response and exhibit antiviral, antiproliferative, and immunomodulatory effects by activation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway signaling [1]. Several small-molecular activators www.impactjournals.com/oncotarget of type I IFNs have been identified through cell-based screening and exhibit antiviral or anti-cancerous effects through various mechanisms, including suppression of cAMP-PKA-SHP2 signaling, inhibition of pyrimidine biosynthesis, and activation of type I IFN receptors [3,4,5]. The 26S proteasome, a molecular complex that catalyzes the degradation of ubiquitinated proteins, participates in negative regulation of JAK/STAT pathway signaling. The negative regulatory effects of IFN-β on osteoclastogenesis are correlated with the expression level of Jak, which is regulated by receptor activator of nuclear factor κB ligand (RANKL) by inducing it for ubiquitination and proteasomal degradation [11]. We determined whether emodin is a potent inhibitor of 26S proteasome that activates type I IFNinduced JAK/STAT signaling through inhibition of 26S proteasome-stimulated IFNAR1 degradation
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