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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

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Journal Food Nutr Res
Date 2016 Jul 1
PMID 27356910
Citations 3
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Abstract

Background: 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.

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 (β5 subunit), caspase site (β1 subunit), and trypsin site (β2 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-α-regulated gene expression. Apigenin inhibited the IFN-α-stimulated ubiquitination and degradation of type I interferon receptor 1 (IFNAR1). Apigenin also sensitized the inhibitory effect of IFN-α on viability of cervical carcinoma HeLa cells.

Conclusion: These results suggest that apigenin potentiates the inhibitory effect of IFN-α 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-α/β.

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References
1.
Voges D, Zwickl P, Baumeister W . The 26S proteasome: a molecular machine designed for controlled proteolysis. Annu Rev Biochem. 2000; 68:1015-68. DOI: 10.1146/annurev.biochem.68.1.1015. View

2.
Chen D, Landis-Piwowar K, Chen M, Dou Q . Inhibition of proteasome activity by the dietary flavonoid apigenin is associated with growth inhibition in cultured breast cancer cells and xenografts. Breast Cancer Res. 2008; 9(6):R80. PMC: 2246179. DOI: 10.1186/bcr1797. View

3.
Vetrivel U, Pilla K . Open discovery: An integrated live Linux platform of Bioinformatics tools. Bioinformation. 2009; 3(4):144-6. PMC: 2637960. DOI: 10.6026/97320630003144. View

4.
Taniguchi T, Takaoka A . A weak signal for strong responses: interferon-alpha/beta revisited. Nat Rev Mol Cell Biol. 2001; 2(5):378-86. DOI: 10.1038/35073080. View

5.
Blank V, Poli C, Marder M, Roguin L . Antiproliferative activity of various flavonoids and related compounds: additive effect of interferon-alpha2b. Bioorg Med Chem Lett. 2003; 14(1):133-6. DOI: 10.1016/j.bmcl.2003.10.029. View