title: Dietary apigenin potentiates the inhibitory effect of interferon-α on cancer cell viability through inhibition of 26S proteasome-mediated interferon receptor degradation.
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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Li
authors.affiliation: Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China.
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Yang
authors.affiliation: School of Chinese Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China.
authors.forename: Yu-Jiao
authors.initials: YJ
authors.lastname: He
authors.affiliation: Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China.|School of Chinese Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
authors.forename: Jun-Mei
authors.initials: JM
authors.lastname: Huang
authors.affiliation: Ningbo Entry-Exit Inspection and Quarantine Bureau Technical Center, Ningbo, China.
authors.forename: Han-Wei
authors.initials: HW
authors.lastname: Liu
authors.affiliation: Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China.
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Shen
authors.affiliation: Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China.|Sichuan Translational Medicine Research Hospital, Chinese Academy of Sciences, Chengdu, China; wangfei@cib.ac.cn.
authors.forename: Fei
authors.initials: F
authors.lastname: Wang
keywords: STAT; apigenin; interferon; proteasome; ubiquitination