A therapeutic dose of doxorubicin activates ubiquitin-proteasome system-mediated proteolysis by acting on both the ubiquitination apparatus and proteasome

Liu, Jinbao; Zheng, Hui; Tang, Mingxin; Ryu, Youn-Chul; Wang, Xuejun

doi:10.1152/ajpheart.01052.2008

Cited by 84 publications

(79 citation statements)

References 53 publications

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“…Perhaps with the exception of viral myocarditis and anthracycline-induced cardiomyopathy (70,85,86), the majority of the studies using animal models have suggested that cardiac proteasome function is impaired/insufficient during the progression of a large subset of heart diseases to CHF. This is best illustrated by cardiac proteinopathy and myocardial I/R injury, although proteasome malfunction has also been observed in other types of cardiomyopathy (6,81,110).…”

Section: Proteasome Dysfunction In Cardiac Diseasesmentioning

confidence: 99%

Proteasome functional insufficiency in cardiac pathogenesis

Wang

Zheng

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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The ubiquitin-proteasome system (UPS) is responsible for the degradation of most cellular proteins. Alterations in cardiac UPS, including changes in the degradation of regulatory proteins and proteasome functional insufficiency, are observed in many forms of heart disease and have been shown to play an important role in cardiac pathogenesis. In the past several years, remarkable progress in understanding the mechanisms that regulate UPS-mediated protein degradation has been achieved. A transgenic mouse model of benign enhancement of cardiac proteasome proteolytic function has been created. This has led to the first demonstration of the necessity of proteasome functional insufficiency in the genesis of important pathological processes. Cardiomyocyte-restricted enhancement of proteasome proteolytic function by overexpression of proteasome activator 28α protects against cardiac proteinopathy and myocardial ischemia-reperfusion injury. Additionally, exciting advances have recently been achieved in the search for a pharmacological agent to activate the proteasome. These breakthroughs are expected to serve as an impetus to further investigation into the involvement of UPS dysfunction in molecular pathogenesis and to the development of new therapeutic strategies for combating heart disease. An interplay between the UPS and macroautophagy is increasingly suggested in noncardiac systems but is not well understood in the cardiac system. Further investigations into the interplay are expected to provide a more comprehensive picture of cardiac protein quality control and degradation.

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Section: Proteasome Dysfunction In Cardiac Diseasesmentioning

confidence: 99%

Proteasome functional insufficiency in cardiac pathogenesis

Wang

Zheng

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…These in vitro and cell-based assays were performed as we previously described (14). A 20 microliter of Tris-HCl buffer (pH 7.4) containing purified 20S proteasome (0.5 ninomolar) (from human erythrocytes, Enzo Life Sciences) or crude protein extracts (10 microgram protein) from the cultured cells were added to a total volume of 180 microliter Tris-HCl (pH 7.4) reaction buffer containing the synthetic fluorogenic peptide Suc-LLVYaminomethylcoumarin (AMC) for the proteasomal chymotrypsin-like activity.…”

Section: Peptidase Activity Assay and Cell-based Proteasome Activity mentioning

confidence: 99%

Sanggenon C decreases tumor cell viability associated with proteasome inhibition

Huang¹

2009

Front Biosci

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Several flavonoids have been reported to be proteasome inhibitors, but whether prenylated flavonoids are able to inhibit proteasome function remains unknown. We report for the first time that Sanggenon C, a natural prenylated flavonoid, inhibits tumor cellular proteasomal activity and cell viability. We found that (1) Sanggenon C inhibited tumor cell viability and induced cell cycle arrest at G0/G1 phase; (2) Sanggenon C inhibited the chymotrypsin-like activity of purified human 20S proteasome and 26S proteasome in H22 cell lysate, and Sanggenon C was able to dosedependently accumulate ubiquitinated proteins and proteasome substrate protein p27; (3) Sanggenon C-induced proteasome inhibition occurred prior to cell death in murine H22 and P388 cell lines; (4) Sanggenon C induced death of human K562 cancer cells and primary cells isolated from leukemic patients. We conclude that Sanggenon C inhibits tumor cell viability via induction of cell cycle arrest and cell death, which is associated with its ability to inhibit the proteasome function and that proteasome inhibition by Sanggenon C at least partially contributes to the observed tumor cell growth-inhibitory activity. Proteasome inhibition has been demonstrated as a novel therapeutic strategy in multiple disease models, including fibrosis (4), inflammation (5), ischemia-reperefusion injury (6), myocardial hypertrophy (7) and cancer (8). Proteasome inhibitor bortezomib (Valcade or PS-341) has been approved by the United States FDA to treat multiple myeloma. Other proteasome inhibitors are now under clinical trials for cancer therapy (8). However, there were some associated toxicity observed in the clinical trials using bortezomib (8). Therefore, there is a need to search for novel proteasome inhibitors with decreased side effect. It is an attractive idea to identify and isolate novel natural proteasome inhibitors from medicinal plants. Many of the reported natural proteasome inhibitors belong to the flavonoid family (3). Among all these reported natural flavonoid proteasome inhibitors, an aromatic ketone structure plays a very important role for binding to the threonine residue at the N terminus (Thr 1) of the proteasome subunits and inhibiting the proteasomal activities (3, 9, 10). KeywordsSeveral flavonoids have been isolated from the stem bark of Morus cathayana (SANGPAIPI), including Sanggenon C. Sanggenon C is a flavanone Diel-Alder adduct compound. Up to now, there are only a few reports on the biological and pharmacological effects of Sanggenon C. It has been reported that Sanggenon C has anti-oxidant and antiinflammation activities (2) and could inhibit TNF-alpha-stimulated cell adhesion and expression of VCAM-1 by suppressing the activation of NF-kappa B. It has also been proposed that Sanggenon C decreases ICAM-1 protein expression at a post-translational level (11). In addition, it was reported that Sanggenon C inhibited protein tyrosine phosphatase 1B (12) and possessed the function to decrease blood pressure. Since Sanggenon C possesses the mo...

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“…β-catenin is an endogenous proteasome substrate (12). Inhibition of proteasome activity by bortezomib was confirmed by accumulation of this known proteasome substrate.…”

Section: Resultsmentioning

confidence: 91%

An autophagy inhibitor enhances the inhibition of cell proliferation induced by a proteasome inhibitor in MCF-7 cells

et al. 2011

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Abstract. The ubiquitin-proteasome system and the autophagy-lysosome pathway are the two main routes for eukaryotic intracellular protein clearance. Inhibition of proteasome activity leads to cell death. Due to the dual roles of autophagy in tumor cell survival and death, the effect of suppression of autophagy on breast cancer cells remains to be elucidated. We investigated whether inhibition of the proteasome is capable of inducing autophagy, and we assessed the effect of combined inhibition of the proteasome and autophagy on human breast cancer MCF-7 cells. The proteasome inhibitor bortezomib was used to induce autophagy in MCF-7 cells, and the effect of autophagy on the proliferation of MCF-7 cells was investigated using the autophagy inhibitor 3-MA. Cell viability was measured by MTT assay. The expression of autophagy-related proteins was determined by Western blot analysis and the GFP-LC3 redistribution was detected using a fluorescence microscope after MCF-7 cells were infected with a GFP-LC3-expressing adenovirus. MCF-7 cell proliferation was inhibited and autophagy was activated in the same dose-dependent manner. Bortezomib induced a dose-dependent increase in LC3-II. However, when MCF-7 cells were co-treated with bortezomib and 3-MA, 3-MA blocked the increase in LC3-II protein expression and led to a significant inhibition of cell proliferation. Inhibition of the proteasome may induce autophagy in human breast cancer MCF-7 cells and 3-MA could inhibit autophagy induced by the proteasome inhibitor. A combination of 3-MA and bortezomib increases cell death. These findings indicate that suppression of the two intracellular degradation systems may shed new light on breast cancer control.

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A therapeutic dose of doxorubicin activates ubiquitin-proteasome system-mediated proteolysis by acting on both the ubiquitination apparatus and proteasome

Cited by 84 publications

References 53 publications

Proteasome functional insufficiency in cardiac pathogenesis

Proteasome functional insufficiency in cardiac pathogenesis

Sanggenon C decreases tumor cell viability associated with proteasome inhibition

An autophagy inhibitor enhances the inhibition of cell proliferation induced by a proteasome inhibitor in MCF-7 cells

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