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important article on a natural flavonoid which causes ubiquinization of her2
ie, it gets it ready for the garbage collector mechanism of the cell which then destroys it. Worth struggling with the big words!:
J Cell Biochem. 2008 Jul 24. [Epub ahead of print]
Quercetin-induced ubiquitination and down-regulation of Her-2/neu.
Jeong JH, An JY, Kwon YT, Li LY, Lee YJ.
Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213.
Her-2/neu (ErbB2) is a transmembrane tyrosine kinase and acts as a co-receptor for the other EGFR family members. It is well known that high expression of Her-2/neu is associated with a poor prognosis in breast cancer. Quercetin, a flavonoid present in many vegetables and fruits, has been studied extensively as a chemoprevention agent in several cancer models. In this study, we observed that quercetin decreased the level of Her-2/neu protein in time- and dose-dependent manners and also inhibited the downstream survival PI3K-Akt signaling pathway in Her-2/neu-overexpressing breast cancer SK-Br3 cells. We also observed that quercetin induced polyubiquitination of Her-2/neu. When the proteasome pathway was blocked by MG-132 during quercetin treatment, accumulation of the NP-40 insoluble form of Her-2/neu occurred. Interestingly, data from immunocomplex studies revealed that quercetin promoted interaction between Her-2/neu and Hsp90 which is a molecular chaperone involved in stabilization of Her-2/neu. In this condition, inhibition of Hsp90 activity by a specific inhibitor, geldanamycin (GA), or intracellular ATP depletion caused dissociation of Hsp90 from Her-2/neu and promoted ubiquitination and down-regulation of Her-2/neu protein. In addition, the carboxyl terminus of Hsc70-interacting protein (CHIP), a chaperone-dependent E3 ubiquitin ligase, played a crucial role in the quercetin-induced ubiquitination of Her-2/neu. Inhibition of tyrosine kinase activity of Her-2/neu by quercetin could indicate an lateration in the Her-2/neu structure which promotes CHIP recruitments and down-regulation of Her-2/neu. We believe that by using quercetin, new therapeutic strategies can be developed to treat Her-2/neu overexpressing cancers. J. Cell. Biochem. (c) 2008 Wiley-Liss, Inc.
PMID: 18655187 [PubMed - as supplied by publisher
from the conclusions:
Besides quercetin, several other natural products are known to have the effect of down-regulating Her-2/neu protein. Among plant flavonoids, apigenin has a potent growth-inhibitory effect and induces apoptosis in Her-2/neu overexpressing breast cancer cells. Apigenin dissociates Her-2/neu from GRP94 and produces reduction of the intracellular level of Her-2/neu through the ubiquitin-proteasome dependent protein degradation pathway [Way et al., [2004]]. Curcumin, a major pigment extracted from the plant Curcuma longa Lin, covalently modifies Her-2/neu and induces CHIP-dependent ubiquitination, but curcumin induces Her-2/neu depletion other than by the proteasomal degradation pathway [Jung et al., [2007]]. Oleic acid (OA; 18:1n-9), the main monounsaturated fatty acid of olive oil, is known to suppress the overexpression of Her-2/neu. In contrast to quercetin, OA exposure specifically represses the transcriptional activity of the Her-2/neu gene promoter; this is due to the up-regulation of the Ets protein PEA3 (a transcriptional repressor of the Her-2/neu gene promoter) by OA [Menendez et al., [2005]]. Compared to these other natural compounds, quercetin induces Her-2/neu down-regulation in a unique manner.
In the treatment of Her-2/neu overexpressing breast cancers, there are two major approaches to targeting Her-2/neu: down-regulation of Her-2/neu protein level using ectodomain-binding antibodies (mAbs) and inhibition of tyrosine kinase activity by small molecule inhibitors that compete with ATP in the tyrosine kinase domain [Imai and Takaoka, [2006]]. In this report, we revealed that quercetin inhibits Her-2/neu tyrosine kinase activity (Fig. 7A-C) and down-regulates Her-2/neu protein level (Fig. 1). It is interesting that the manner in which quercetin down-regulates Her-2/neu protein is very similar to that of the CI-1033 tyrosine kinase inhibitor [Citri et al., [2002]]. Along with inhibition of tyrosine phosphorylation, CI-1033 enhances ubiquitylation and accelerates endocytosis and subsequent intracellular degradation of Her-2/neu protein. The degradative pathway stimulated by tyrosine kinase inhibitors appears to be chaperone mediated. Similar to quercetin and GA, CI-1033 and GA additively inhibit tumor cell growth [Citri et al., [2002]]. We believe that, as shown in the study of CI-1033, an understanding of the dual inhibitory function of quercetin advances clinical application, allowing effective therapeutic and preventive studies to be initiated.
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