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Dietary apigenin potentiates the inhibitory effect of interferon-? on cancer cell viability through inhibition of 26S proteasome-mediated interferon receptor degradation.

ABSTRACT: BACKGROUND:Type I interferons (IFN-?/?) have broad and potent immunoregulatory and antiproliferative activities. However, it is still known whether the dietary flavonoids exhibit their antiviral and anticancer properties by modulating the function of type I IFNs. OBJECTIVE:This study aimed at determining the role of apigenin, a dietary plant flavonoid abundant in common fruits and vegetables, on the type I IFN-mediated inhibition of cancer cell viability. DESIGN:Inhibitory effect of apigenin on human 26S proteasome, a known negative regulator of type I IFN signaling, was evaluated in vitro. Molecular docking was conducted to know the interaction between apigenin and subunits of 26S proteasome. Effects of apigenin on JAK/STAT pathway, 26S proteasome-mediated interferon receptor stability, and cancer cells viability were also investigated. RESULTS:Apigenin was identified to be a potent inhibitor of human 26S proteasome in a cell-based assay. Apigenin inhibited the chymotrypsin-like, caspase-like, and trypsin-like activities of the human 26S proteasome and increased the ubiquitination of endogenous proteins in cells. Results from computational modeling of the potential interactions of apigenin with the chymotrypsin site (?5 subunit), caspase site (?1 subunit), and trypsin site (?2 subunit) of the proteasome were consistent with the observed proteasome inhibitory activity. Apigenin enhanced the phosphorylation of signal transducer and activator of transcription proteins (STAT1 and STAT2) and promoted the endogenous IFN-?-regulated gene expression. Apigenin inhibited the IFN-?-stimulated ubiquitination and degradation of type I interferon receptor 1 (IFNAR1). Apigenin also sensitized the inhibitory effect of IFN-? on viability of cervical carcinoma HeLa cells. CONCLUSION:These results suggest that apigenin potentiates the inhibitory effect of IFN-? on cancer cell viability by activating JAK/STAT signaling pathway through inhibition of 26S proteasome-mediated IFNAR1 degradation. This may provide a novel mechanism for increasing the efficacy of IFN-?/?.

SUBMITTER: Li S

PROVIDER: S-EPMC4928072 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Dietary apigenin potentiates the inhibitory effect of interferon-α on cancer cell viability through inhibition of 26S proteasome-mediated interferon receptor degradation.

Li Sheng S Yang Li-Juan LJ Wang Ping P He Yu-Jiao YJ Huang Jun-Mei JM Liu Han-Wei HW Shen Xiao-Fei XF Wang Fei F

Food & nutrition research 20160628

<h4>Background</h4>Type I interferons (IFN-α/β) have broad and potent immunoregulatory and antiproliferative activities. However, it is still known whether the dietary flavonoids exhibit their antiviral and anticancer properties by modulating the function of type I IFNs.<h4>Objective</h4>This study aimed at determining the role of apigenin, a dietary plant flavonoid abundant in common fruits and vegetables, on the type I IFN-mediated inhibition of cancer cell viability.<h4>Design</h4>Inhibitory ...[more]

PMID: 27356910

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Project description:All eukaryotes rely on selective proteolysis to control the abundance of key regulatory proteins and maintain a healthy and properly functioning proteome. Most of this turnover is catalyzed by the 26S proteasome, an intricate, multi-subunit proteolytic machine. Proteasomes recognize and degrade proteins first marked with one or more chains of poly-ubiquitin, the addition of which is actuated by hundreds of ligases that individually identify appropriate substrates for ubiquitylation. Subsequent proteasomal digestion is essential and influences a myriad of cellular processes in species as diverse as plants, fungi and humans. Importantly, dysfunction of 26S proteasomes is associated with numerous human pathologies and profoundly impacts crop performance, thus making an understanding of proteasome dynamics critically relevant to almost all facets of human health and nutrition. Given this widespread significance, it is not surprising that sophisticated mechanisms have evolved to tightly regulate 26S proteasome assembly, abundance and activity in response to demand, organismal development and stress. These include controls on transcription and chaperone-mediated assembly, influences on proteasome localization and activity by an assortment of binding proteins and post-translational modifications, and ultimately the removal of excess or damaged particles via autophagy. Intriguingly, the autophagic clearance of damaged 26S proteasomes first involves their modification with ubiquitin, thus connecting ubiquitylation and autophagy as key regulatory events in proteasome quality control. This turnover is also influenced by two distinct biomolecular condensates that coalesce in the cytoplasm, one attracting damaged proteasomes for autophagy, and the other reversibly storing proteasomes during carbon starvation to protect them from autophagic clearance. In this review, we describe the current state of knowledge regarding the dynamic regulation of 26S proteasomes at all stages of their life cycle, illustrating how protein degradation through this proteolytic machine is tightly controlled to ensure optimal growth, development and longevity.

Dataset Information

Dietary apigenin potentiates the inhibitory effect of interferon-? on cancer cell viability through inhibition of 26S proteasome-mediated interferon receptor degradation.

Publications

Dietary apigenin potentiates the inhibitory effect of interferon-α on cancer cell viability through inhibition of 26S proteasome-mediated interferon receptor degradation.

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