Inhibitory Effect of Flavonoids on 26S Proteasome Activity

Abstract

Inhibiting proteasomal degradation has been shown to induce apoptosis in tumor cells. Utilization of proteasome inhibition is therefore one approach to anticancer therapy. Some of the flavonoids can induce cell apoptosis via inhibiting proteasome 26S activity. In this study, the inhibition of 26S proteasome from pig red blood cells was analyzed on 12 flavones, 5 flavanones, and 9 isoflavones by using a proteolysis assay. Several flavonoids such as apigenin-6-hydroxy-7-O-beta-D-glucoside, quercetin, rutin, 6-hydroxyapigenin, 5,6,4'-trihydroxy-7,3'-dimethoxyflavone, 5,6,3',4'-tetrahydroxy-7-methoxyflavone, glycitecin, and 6,7,4'-trihydroxyisoflavone inhibited the chymotrypsin-like, caspase-like, or trypsin-like activity of 26S proteasome when Suc-LLVY-AMC, Z-LLE-AMC, and Ac-RLR-AMC were used as substrates. Three peptidase activities of flavonoids were found to be significantly correlated with one another. Flavones had significantly stronger inhibitory effects on chymotrypsin-like and caspase-like activities than flavanones and isoflavones. 5,6,3',4'-Tetrahydroxy-7-methoxyflavone, 5,6,4'-trihydroxy-7,3'-dimethoxyflavone, and quercetin displayed a mixed type inhibition of 26S by Lineweaver-Burk plots analysis. Furthermore, 5,6,3',4'-tetrahydroxy-7-methoxyflavone is found to have a higher inhibitory effect on 26S proteasome activities and is the only flavonoid to inhibit all three peptidase activities, whereas the inhibition of flavonoids was not affected by ubiquitin-induced stimulation of the three peptidase activities of 26S proteasome; 5,6,3',4'-tetrahydroxy-7-methoxyflavone inhibited 75% casein degradation. These results suggest that both the 6-hydroxy and 7-methoxy positions of the flavone may play an important role in targeting 26S activity.

Quercetin downregulates Mcl-1 by acting on mRNA stability and protein degradation

“…In addition, quercetin-induced polyubiquitination of Her-2/neu, the elevated expression level of which is associated with poor prognosis in breast cancer, decreasing its protein level in a time- and dose-dependent manner (Jeong et al , 2008). However, these data contrast with other results suggesting that flavonoids might act as proteasome inhibitors decreasing cancer risk in tumours in which proteasome activity is required for cancer cell survival (Chen et al , 2005; Chang, 2009). Moreover, in a recent paper, Liu et al (2008) demonstrated that quercetin was able to inhibit the effect of bortezomib in CLL patients because of its ability to bind to the boronic acid group of that molecule.…”

Synthesis and activity of endomorphin-2 and morphiceptin analogues with proline surrogates in position 2

“…Although several endogenous peptide ligands of opioid receptors are known most of them, including enkephalins, does not show significant μ-selective agonistic activity. A notable exception is represented by morphiceptin, a tetrapeptide amide (Tyr–Pro–Phe–Pro–NH 2 ) isolated from an enzymatic digest of bovine β-casein [1–3] and by the structurally related opioid ligands endomorphin-1 (EM1: Tyr–Pro–Trp–Phe–NH 2 ) and endomorphin-2 (EM2: Tyr–Pro–Phe–Phe–NH 2 ) which exhibit high μ-opioid receptor selectivity and agonist potency [4]. …”

“…EM2 and morphiceptin have a different C-terminal address sequence [3] which is –Phe–NH 2 for EM2 and –Pro–NH 2 for morphiceptin, but an identical Tyr–Pro–Phe– N-terminal message sequence. This feature, common to EMs and morphiceptin, is different from that found in enkephalins and other endogenous opioid peptides such as endorphins and dynorphins.…”

Lumbee traditional medicine: Neuroprotective activities of medicinal plants used to treat Parkinson's disease-related symptoms

“…Some polyphenols have been reported to engage in redox cycling reactions, resulting in a build-up of ROS that react with key regulatory cysteine residues of Keap1, whereas others are thought to activate Nrf2 transcriptional activity by reacting directly with Keap1 (Erlank et al, 2011; Kumar et al, 2014; Satoh et al, 2013). As a second possible mechanism, some polyphenols have been shown to inhibit the UPS (Chang, 2009; Murakami, 2013; Pettinari et al, 2006). Nrf2 is degraded by the UPS, and inhibition of the UPS has been linked to up-regulation of Nrf2 activity and an increase in glutathione levels (Chen and Regan, 2005; Yamamoto et al, 2007).…”

“…A number of polyphenols, including elderflower polyphenols listed in Table 3, have been shown to interfere with UPS activity (Chang, 2009; Shen et al, 2012). The flavonol quercetin has been shown to inhibit the chymotrypsin-like activity of purified 20S and 26S proteasome in Jurkat T cells (Chen et al, 2005).…”