Xanthohumol Impairs Autophagosome Maturation through Direct Inhibition of Valosin-Containing Protein

Faculty of Science and Technology, Department of Biosciences and Informatics, Keio University, Yokohama 223-8522, Japan.
ACS Chemical Biology (Impact Factor: 5.33). 03/2012; 7(5):892-900. DOI: 10.1021/cb200492h
Source: PubMed


Autophagy is a bulk, nonspecific protein degradation pathway that is involved in the pathogenesis of cancer and neurodegenerative disease. Here, we observed that xanthohumol (XN), a prenylated chalcone present in hops (Humulus lupulus L.) and beer, modulates autophagy. By using XN-immobilized beads, valosin-containing protein (VCP) was identified as a XN-binding protein. VCP has been reported to be an essential protein for autophagosome maturation. Using an in vitro pull down assay, we showed that XN bound directly to the N domain, which is known to mediate cofactor and substrate binding to VCP. These data indicated that XN inhibited the function of VCP, thereby allowing the impairment of autophagosome maturation and resulting in the accumulation of microtubule-associated protein 1 light chain 3-II (LC3-II). This is the first report demonstrating XN as a VCP inhibitor that binds directly to the N domain of VCP. Our finding that XN bound to and inactivated VCP not only reveals the molecular mechanism of XN-modulated autophagy but may also explain how XN exhibits various biological activities that have been reported previously.

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    • "Apart from the broad spectrum of biological activity of prenylated hop flavonoids that have been described here, it is important to mention some other valuable properties of these compounds, such as for example their antiviral activity [109] [110] [111], among them anti-HIV-1 one [112]. Moreover, prenylated hop flavonoids stimulate iodide uptake in rat thyroid-derived FRTL-5 cells [113], modulate hepatic expression of genes involved in thyroid hormone distribution and metabolism [114], activate constitutive androstane receptor (CAR) [115], prevent platelet activation in human platelets [116], prevent disuse muscle atrophy [117], impair autophagosome maturation through direct inhibition of valosin-containing protein [118], promote neuroprotective activity in ischemic stroke in rats [119], enhance neuronal differentiation and neurite outgrowth and have neuroprotective activity in vitro [120], attenuate atherosclerosis in mice [121] and also inhibit rumen methanogenesis [122]. Besides of all the described biological activity, it is worth mentioning that compounds 1 and 28 positively accumulated and reached liver and mammary glands after oral administration of hop extracts containing 1, 22, 27, 28 to Sprague–Dawley rats. "
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    • "If a specific p97/CDC-48 inhibitor is available, it will be also useful as another tool for the detailed analysis of p97/CDC-48 function both in vitro and in vivo. Seven p97/CDC-48 inhibitors have been reported so far: (1) Eeyarestatin I [82], (2) 2-Anilino-4-aryl-1,3-thiazole [8], (3) the Syk inhibitor III [11], (4) N2,N4-dibenzylquinazoline-2,4-diamine (DBeQ) [11] [13], (5) Sorafenib [100], (6) alkylsulfanyl-1,2,4-triazoles [58] and (7) Xanthohumol [69] "
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