Hieronymus H, Lamb J, Ross KN, Peng XP, Clement C, Rodina A, Nieto M, Du J, Stegmaier K, Raj SM, Maloney KN, Clardy J, Hahn WC, Chiosis G, Golub TRGene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators. Cancer Cell 10: 321-330

The Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
Cancer Cell (Impact Factor: 23.52). 11/2006; 10(4):321-30. DOI: 10.1016/j.ccr.2006.09.005
Source: PubMed


Although androgen receptor (AR)-mediated signaling is central to prostate cancer, the ability to modulate AR signaling states is limited. Here we establish a chemical genomic approach for discovery and target prediction of modulators of cancer phenotypes, as exemplified by AR signaling. We first identify AR activation inhibitors, including a group of structurally related compounds comprising celastrol, gedunin, and derivatives. To develop an in silico approach for target pathway identification, we apply a gene expression-based analysis that classifies HSP90 inhibitors as having similar activity to celastrol and gedunin. Validating this prediction, we demonstrate that celastrol and gedunin inhibit HSP90 activity and HSP90 clients, including AR. Broadly, this work identifies new modes of HSP90 modulation through a gene expression-based strategy.

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    • "Determining the mRNA levels of various target genes of NF-kB pathways showed no difference in the hypothalamus of vehicle-or Celastroltreated mice (Figure S4A). Celastrol has also been proposed as a heat-shock protein 90 kDa (HSP90) inhibitor (Hieronymus et al., 2006). HSP70 protein level is an indicator of HSP90 activity, and inhibition of HSP90 leads to increase in HSP70 "
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    ABSTRACT: Despite all modern advances in medicine, an effective drug treatment of obesity has not been found yet. Discovery of leptin two decades ago created hopes for treatment of obesity. However, development of leptin resistance has been a big obstacle, mitigating a leptin-centric treatment of obesity. Here, by using in silico drug-screening methods, we discovered that Celastrol, a pentacyclic triterpene extracted from the roots of Tripterygium Wilfordi (thunder god vine) plant, is a powerful anti-obesity agent. Celastrol suppresses food intake, blocks reduction of energy expenditure, and leads to up to 45% weight loss in hyperleptinemic diet-induced obese (DIO) mice by increasing leptin sensitivity, but it is ineffective in leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mouse models. These results indicate that Celastrol is a leptin sensitizer and a promising agent for the pharmacological treatment of obesity. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell 05/2015; 161(5):999-1011. DOI:10.1016/j.cell.2015.05.011 · 32.24 Impact Factor
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    • "In addition, a recent pharmacological study of AR signaling using gene expression profiling indicated two more classes of drugs that might inhibit chaperone/co-chaperone interactions. Two drug families, centering on the natural compounds celastrol and gedunin, were uncovered [182]. Celastrol was shown to disrupt the function of the Hsp90/Cdc37 complex, a key growth-requiring pathway in prostate cancer and thus is a promising agent for this disease [183]. "
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    ABSTRACT: Molecular chaperones play important roles in all cellular organisms by maintaining the proteome in an optimally folded state. They appear to be at a premium in cancer cells whose evolution along the malignant pathways requires the fostering of cohorts of mutant proteins that are employed to overcome tumor suppressive regulation. To function at significant rates in cells, HSPs interact with cochaperones, proteins that assist in catalyzing individual steps in molecular chaperoning as well as in posttranslational modification and intracellular localization. We review current knowledge regarding the roles of chaperones such as heat shock protein 90 (Hsp90) and Hsp70 and their cochaperones in cancer. Cochaperones are potential targets for cancer therapy in themselves and can be used to assess the likely prognosis of individual malignancies. Hsp70 cochaperones Bag1, Bag3, and Hop play significant roles in the etiology of some cancers as do Hsp90 cochaperones Aha1, p23, Cdc37, and FKBP1. Others such as the J domain protein family, HspBP1, TTC4, and FKBPL appear to be associated with more benign tumor phenotypes. The key importance of cochaperones for many pathways of protein folding in cancer suggests high promise for the future development of novel pharmaceutical agents.
    04/2013; 2013(22):217513. DOI:10.1155/2013/217513
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    • "In order to elucidate the correlation between the HSP90-targeting effects [27] and the Noxa induction in Celastrol-exposed cells, the degradation of Hsp90 client proteins, such as phospho ERK1/2 and CDK4, was monitored by western blotting in both Bel-7402 and HepG2 cells with serial concentrations of celastrol for 3 h (Fig. 6A and 6B). Additionally, in accordance with previous report, Celastrol also increased Hsp70 expression, which is a hallmark of Hsp90 inhibition [28]. "
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    ABSTRACT: The human hepatocellular carcinoma (HCC) represents biologically aggressive and chemo-resistant cancers. Owing to the low affinity with the apoptotic factor Mcl-1, the BH3 mimetic drug ABT-737 failed to exert potent cancer-killing activities in variety of cancer models including HCC. The current study demonstrated that combining ABT-737 and Celastrol synergistically suppressed HCC cell proliferation, and induced apoptosis which was accompanied with the activation of caspase cascade and release of cytochrome c from mitochondria. Further study revealed that the enhanced Noxa caused by Celastrol was the key factor for the synergy, since small interfering RNA-mediated knockdown of Noxa expression in HCC cells resulted in decreased apoptosis and attenuated anti-proliferative effects of the combination. In addition, our study unraveled that, upon Celastrol exposure, the activation of endoplasmic reticulum (ER) stress, specifically, the eIF2α-ATF4 pathway played indispensable roles in the activation of Noxa, which was validated by the observation that depletion of ATF4 significantly abrogated the Noxa elevation by Celastrol. Our findings highlight a novel signaling pathway through which Celastrol increase Noxa expression, and suggest the potential use of ATF4-mediated regulation of Noxa as a promising strategy to improve the anti-cancer activities of ABT-737.
    PLoS ONE 12/2012; 7(12):e52333. DOI:10.1371/journal.pone.0052333 · 3.23 Impact Factor
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