Xanthohumol Impairs Autophagosome Maturation through Direct Inhibition of Valosin-Containing Protein
ABSTRACT 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.
- SourceAvailable from: Agnieszka Bartmańska
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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   , among them anti-HIV-1 one . Moreover, prenylated hop flavonoids stimulate iodide uptake in rat thyroid-derived FRTL-5 cells , modulate hepatic expression of genes involved in thyroid hormone distribution and metabolism , activate constitutive androstane receptor (CAR) , prevent platelet activation in human platelets , prevent disuse muscle atrophy , impair autophagosome maturation through direct inhibition of valosin-containing protein , promote neuroprotective activity in ischemic stroke in rats , enhance neuronal differentiation and neurite outgrowth and have neuroprotective activity in vitro , attenuate atherosclerosis in mice  and also inhibit rumen methanogenesis . 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. "
ABSTRACT: In this review we aim to present current knowledge on biotransformation of flavonoids from hop cones with respect to type of product, catalyst and conversion. Subsequently, a comparative analysis of biological activity of prenylated hop flavonoids and their biotransformation products has been performed in order to indicate these research efforts that have good potential for application in pharmaceutical industry. There is increasing evidence that the products of biotransformation of hop prenylflavonoids, which have been little studied until recently, can be used as drugs or drug ingredients and also as standards of human drug metabolites. They can also serve as an inspiration for the design and chemical synthesis of new derivatives with higher or different biological activity. Nevertheless, much additional work, among others on determining the mechanism of action in in vivo systems, is needed to open up the way to biomedical application of these compounds.Current Drug Metabolism 12/2013; 14(10). DOI:10.2174/1389200214666131211151855 · 3.49 Impact Factor
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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 , (2) 2-Anilino-4-aryl-1,3-thiazole , (3) the Syk inhibitor III , (4) N2,N4-dibenzylquinazoline-2,4-diamine (DBeQ)  , (5) Sorafenib , (6) alkylsulfanyl-1,2,4-triazoles  and (7) Xanthohumol  "
ABSTRACT: P97/CDC-48 is a prominent member of a highly evolutionary conserved Walker cassette - containing AAA+ ATPases. It has been involved in numerous cellular processes ranging from the control of protein homeostasis to membrane trafficking through the intervention of specific accessory proteins. Expression of p97/CDC-48 in cancers has been correlated with tumor aggressiveness and prognosis, however the precise underlying molecular mechanisms remain to be characterized. Moreover p97/CDC-48 inhibitors were developed and are currently under intense investigation as anticancer drugs. Herein, we discuss the role of p97/CDC-48 in cancer development and its therapeutic potential in tumor cell biology.Cancer letters 05/2013; 337. DOI:10.1016/j.canlet.2013.05.030 · 5.62 Impact Factor
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ABSTRACT: The aim of this study was to analyze the diversity and consistency of regulatory signaling in cancer cell migration, using a chemical genomic approach. The effects of 34 small molecular compounds were assessed quantitatively by wound healing assay in ten types of migrating cells. Hierarchical clustering was performed on the subsequent migration inhibition profile of the compounds and cancer cell types. The result was that hierarchical clustering accurately classified the compounds according to their targets. Furthermore, the cancer cells tested in this study were classified into three clusters, and the compounds were grouped into four clusters. An inhibitor of JNK suppressed all types of cell migration; however, inhibitors of ROCK, GSK-3 and p38MAPK only inhibited the migration of a subset of cell lines. Thus, our analytical system could easily distinguish between the common and cell type-specific signals responsible for cell migration.Scientific Reports 11/2012; 2:823. DOI:10.1038/srep00823 · 5.58 Impact Factor