Celastrol regulates multiple nuclear transcription factors belonging to HSP90's clients in a dose- and cell type-dependent way

Zhang, Denghai; Xu, Limin; Cao, Fanfan; Wei, Tingxuan; Yang, Chen; Uzan, Georges; Peng, Bin

doi:10.1007/s12192-010-0202-1

Cited by 26 publications

(16 citation statements)

References 34 publications

(49 reference statements)

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“…Although several reports mentioned about the involvement of celastrol in apoptosis of hepatoma cells, no study has been reported the anti-metastatic function of celastrol in HCC [25,26]. In this study, we investigated the effect of celastrol on migration and invasion ability of HCC cells.…”

Section: Discussionmentioning

confidence: 99%

miR-224 is Critical for Celastrol-Induced Inhibition of Migration and Invasion of Hepatocellular Carcinoma Cells

Liú

et al. 2013

Cell Physiol Biochem

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Background/Aims: The molecular mechanisms of celastrol on hepatocellular carcinoma (HCC) cells migration and invasion ability is the major problem that prompted the study. Methods: We first evaluated the effect of celastrol on migration and invasion ability of HepG2 cells using transwell migration and matrigel invasion assays. Next, we assessed the effect of celastrol on NF-κB transcriptional activity in hepatocellular carcinoma cells using western blot and luciferase reporter assay. We also performed real-time PCR to measure miR-224, MMP-2 and MMP-9 expression. Western blot was used to measure protein expression of MMP-2 and MMP-9. Furthermore, we used miR-224 inhibitor to evaluate whether down-regulation of miR-224 expression can affect MMP-2 and MMP-9 expression. The binding ability of p65/NF-κB on the miR-224 promote has been assessed by chromatin immunoprecipitation and quantitative real-time PCR (ChIP-qPCR). Finally, we evaluated the effect of miR-224 on celastrol-induced anti-tumor activity using miR-224 precursor. Results: Celastrol significantly impaired migration and invasion of HepG2 cells and inhibited the activation of NF-κB and Akt in dose-dependent manner. IGF (the strong stimulator of Akt) inhibited the transcriptional activity of NF-κB in cells treated with celastrol. Besides, celastrol efficiently decreased the expression of miR-224 and protein expression of MMP-2 and MMP-9. ChIP-qPCR showed that p65/NF-κB binding to the miR-224 promoter sharply decreased after exposure to celastrol in time-dependent manner. Furthermore, inhibition of miR-224 expression can decrease MMP-9 protein level. Most importantly, miR-224 precursor can reverse the effect of celastrol on impairment of migration and invasion in HepG2 and Huh7 cells. Conclusion: Celastrol treatment inhibits migration and invasion of HCC cell and that the effect is partly due to NF-κB regulating miR-224 expression.

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Section: Discussionmentioning

confidence: 99%

miR-224 is Critical for Celastrol-Induced Inhibition of Migration and Invasion of Hepatocellular Carcinoma Cells

Liú

et al. 2013

Cell Physiol Biochem

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“…Nevertheless, it was very confusing that Rottlerin was positive with metformin in our result, because Rottlerin could inhibit insulin-stimulated glucose transport in 3T3-L1 adipocytes by uncoupling mitochondrial oxidative phosphorylation [41]. Besides, Zhang et al suggested new possible applications (drug repositioning) for Celastrol, such as diabetes management [42]. …”

Section: Resultsmentioning

confidence: 94%

A cross-species analysis method to analyze animal models' similarity to human's disease state

Zheng

et al. 2012

BMC Syst Biol

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BackgroundAnimal models are indispensable tools in studying the cause of human diseases and searching for the treatments. The scientific value of an animal model depends on the accurate mimicry of human diseases. The primary goal of the current study was to develop a cross-species method by using the animal models' expression data to evaluate the similarity to human diseases' and assess drug molecules' efficiency in drug research. Therefore, we hoped to reveal that it is feasible and useful to compare gene expression profiles across species in the studies of pathology, toxicology, drug repositioning, and drug action mechanism.ResultsWe developed a cross-species analysis method to analyze animal models' similarity to human diseases and effectiveness in drug research by utilizing the existing animal gene expression data in the public database, and mined some meaningful information to help drug research, such as potential drug candidates, possible drug repositioning, side effects and analysis in pharmacology. New animal models could be evaluated by our method before they are used in drug discovery.We applied the method to several cases of known animal model expression profiles and obtained some useful information to help drug research. We found that trichostatin A and some other HDACs could have very similar response across cell lines and species at gene expression level. Mouse hypoxia model could accurately mimic the human hypoxia, while mouse diabetes drug model might have some limitation. The transgenic mouse of Alzheimer was a useful model and we deeply analyzed the biological mechanisms of some drugs in this case. In addition, all the cases could provide some ideas for drug discovery and drug repositioning.ConclusionsWe developed a new cross-species gene expression module comparison method to use animal models' expression data to analyse the effectiveness of animal models in drug research. Moreover, through data integration, our method could be applied for drug research, such as potential drug candidates, possible drug repositioning, side effects and information about pharmacology.

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“…The in vivo anti-inflammatory effects of this triterpene have been demonstrated in animal models of collagen-induced arthritis, rheumatoid arthritis, Alzheimer's disease, asthma, and systemic lupus erythematosus [83][84][85]. This triterpene has also been found to suppress tumor initiation, promotion and metastasis in various cancer models through modulation of multiple pro-inflammatory cytokines, chemokines, enzymes and transcription factors [4,[86][87][88][89][90][91]. For example, celastrol has been shown to inhibit the proliferation of a wide variety of tumor cells [6,83,[92][93][94].…”

Section: Celastrolmentioning

confidence: 98%

Targeted inhibition of tumor proliferation, survival, and metastasis by pentacyclic triterpenoids: Potential role in prevention and therapy of cancer

et al. 2012

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a b s t r a c tOver the last two decades, extensive research on plant-based medicinal compounds has revealed exciting and important pharmacological properties and activities of triterpenoids. Fruits, vegetables, cereals, pulses, herbs and medicinal plants are all considered to be biological sources of these triterpenoids, which have attracted great attention especially for their potent anti-inflammatory and anti-cancer activities. Published reports in the past have described the molecular mechanism(s) underlying the various biological activities of triterpenoids which range from inhibition of acute and chronic inflammation, inhibition of tumor cell proliferation, induction of apoptosis, suppression of angiogenesis and metastasis. However systematic analysis of various pharmacological properties of these important classes of compounds has not been done. In this review, we describe in detail the pre-clinical chemopreventive and therapeutic properties of selected triterpenoids that inhibit multiple intracellular signaling molecules and transcription factors involved in the initiation, progression and promotion of various cancers. Molecular targets modulated by these triterpenoids comprise, cytokines, chemokines, reactive oxygen intermediates, oncogenes, inflammatory enzymes such as COX-2, 5-LOX and MMPs, anti-apoptotic proteins, transcription factors such as NF-jB, STAT3, AP-1, CREB, and Nrf2 (nuclear factor erythroid 2-related factor) that regulate tumor cell proliferation, transformation, survival, invasion, angiogenesis, metastasis, chemoresistance and radioresistance. Finally, this review also analyzes the potential role of novel synthetic triterpenoids identified recently which mimic natural triterpenoids in physical and chemical properties and are moving rapidly from bench to bedside research.

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Celastrol regulates multiple nuclear transcription factors belonging to HSP90's clients in a dose- and cell type-dependent way

Cited by 26 publications

References 34 publications

miR-224 is Critical for Celastrol-Induced Inhibition of Migration and Invasion of Hepatocellular Carcinoma Cells

miR-224 is Critical for Celastrol-Induced Inhibition of Migration and Invasion of Hepatocellular Carcinoma Cells

A cross-species analysis method to analyze animal models' similarity to human's disease state

Targeted inhibition of tumor proliferation, survival, and metastasis by pentacyclic triterpenoids: Potential role in prevention and therapy of cancer

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