Emodin potentiates the antiproliferative effect of interferon α/β by activation of JAK/STAT pathway signaling through inhibition of the 26S proteasome
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Yujiao He1, Junmei Huang1,2, Ping Wang2, Xiaofei Shen1, Sheng Li1, Lijuan Yang1, Wanli Liu4, Apichart Suksamrarn3, Guolin Zhang1,5, Fei Wang1,5
1Key Laboratory of Natural Medicine and Clinical Translation, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China
2School of Chinese Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
3Department of Chemistry and Center for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok, Thailand
4MOE Key Laboratory of Protein Science, School of Life Sciences, Tsinghua University, Beijing, China
5Sichuan Translational Medicine Research Hospital, Chinese Academy of Sciences, Chengdu, China
Guolin Zhang, e-mail: email@example.com
Fei Wang, e-mail: firstname.lastname@example.org
Keywords: emodin, interferon, JAK/STAT, 26S proteasome
Received: May 18, 2015 Accepted: November 29, 2015 Published: December 14, 2015
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.
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