Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators

Hieronymus, Haley; Lamb, Justin; Ross, Kenneth N.; Peng, Xiao; Clement, Cristina C.; Rodina, Anna; Nieto, Manuel; Du, Jinyan; Stegmaier, Kimberly; Raj, Srilakshmi M.; Maloney, Katherine N.; Clardy, Jon; Hahn, William C.; Chiosis, Gabriela; Golub, Todd R.

doi:10.1016/j.ccr.2006.09.005

Cited by 570 publications

(573 citation statements)

References 46 publications

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“…Previous studies have shown that celastrol (Fig. 1A), a quinone methide triterpene from Tripterygium wilfordii Hook F regulated the Hsp90 pathway and induced the heat shock response similar to other Hsp90 inhibitors (12,13). We found that celastrol did not effect ATP binding to Hsp90.…”

Section: Introductionsupporting

confidence: 57%

“…However, celastrol did not interrupt the Hsp90-p23 complex in pancreatic cancer cells (Fig. 3A and B), although different results have been reported in SKBR-3 cells (13). The computer modeling also showed p23 blocked the access of celastrol to its binding site in the Hsp90/p23 complex (Fig.…”

Section: Discussionmentioning

confidence: 60%

“…Equal amounts of total protein were subjected to SDS-PAGE, transferred onto nitrocellulose membranes, and probed with appropriate antibodies. Immunoprecipitation was done as described previously (13).…”

Section: Western Blotting and Immunoprecipitationmentioning

confidence: 99%

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A novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex against pancreatic cancer cells

Zhang

Hamza

Cao

et al. 2008

Molecular Cancer Therapeutics

337

320

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Pancreatic cancer is an aggressive disease with multiple biochemical and genetic alterations. Thus, a single agent to hit one molecular target may not be sufficient to treat this disease. The purpose of this study is to identify a novel Hsp90 inhibitor to disrupt protein-protein interactions of Hsp90 and its cochaperones for down-regulating many oncogenes simultaneously against pancreatic cancer cells. Here, we reported that celastrol disrupted Hsp90-Cdc37 interaction in the superchaperone complex to exhibit antitumor activity in vitro and in vivo. Molecular docking and molecular dynamic simulations showed that celastrol blocked the critical interaction of Glu 33 (Hsp90) and Arg 167 (Cdc37). Immunoprecipitation confirmed that celastrol (10 Mmol/L) disrupted the Hsp90-Cdc37 interaction in the pancreatic cancer cell line Panc-1. In contrast to classic Hsp90 inhibitor (geldanamycin), celastrol (0.1-100 Mmol/L) did not interfere with ATP binding to Hsp90. However, celastrol (1-5 Mmol/L) induced Hsp90 client protein degradation (Cdk4 and Akt) by 70% to 80% and increased Hsp70 expression by 12-fold. Celastrol induced apoptosis in vitro and significantly inhibited tumor growth in Panc-1 xenografts. Moreover, celastrol (3 mg/kg) effectively suppressed tumor metastasis by more than 80% in RIP1-Tag2 transgenic mouse model with pancreatic islet cell carcinogenesis. The data suggest that celastrol is a novel Hsp90 inhibitor to disrupt Hsp90-Cdc37 interaction against pancreatic cancer cells.

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Section: Introductionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 60%

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A novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex against pancreatic cancer cells

Zhang

Hamza

Cao

et al. 2008

Molecular Cancer Therapeutics

337

320

View full text Add to dashboard Cite

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“…64 This multi-step study design first required identifying a molecular signature associated with androgen repression by using the hormone-sensitive LNCaP PCA cell line and comparing gene expression profiles with and without the presence of androgen. After identification of 27 AR genes associated with the androgen-repressed state, 65 a bead-based multiplex assay (Luminex Beads) was developed to identify which genes from approximately 2500 compounds produced the same expression signature in LNCaP cells as was originally observed by androgen deprivation.…”

Section: Novel Chemical Genomics Approaches To Identifying Regulatorsmentioning

confidence: 99%

Targeted therapy of cancer: new roles for pathologists—prostate cancer

Rubin

2008

Modern Pathology

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The clinical dilemma today in the management of prostate cancer (PCA) is to distinguish men who need definitive treatment from men who have indolent disease. As demonstrated most recently by the randomized Scandinavian trial evaluating the benefit of prostatectomy over Watchful Waiting, surgery significantly decreased the risk of death from PCA. However, this same study also suggests that 19 men need to be treated to benefit one man. Given the high prevalence of the disease, the aging of the population, and the potential morbidity of treatment, the ability to distinguish aggressive from indolent forms of PCA is critical. Treatment for advanced PCA begins with androgen ablation, but eventually hormone-refractory (HR) PCA emerges. Novel therapies are in various stages of clinical trials, including kinase inhibitors, antisense oligonucleotides, and inhibitors of heat-shock proteins. The discovery of novel therapeutic approaches is an active area of clinical research. Eliminating HR PCA before it advances is a high priority in the biomarker field. Therefore, the development of molecular signatures of lethal PCA are critical. In addition, the recent discovery that a significant percentage of PCAs harbor a TMPRSS2-ETS gene fusion suggests that targeting either the ETS transcription factors or the fusion product may offer a novel approach to therapy. However, in 2007, the mainstay of treatment for advanced PCA remains androgen ablation therapy as originally introduced in the early 1940s.

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“…16 High-throughput screening for androgen signalling inhibitors has identified Celastrol in blocking the interactions between HSP90 and co-chaperone Cdc37/p23. 17 Yang et al demonstrated the inhibitory effect of Celastrol on rabbit 20S proteasomes and elicited cell apoptosis in prostate cancer cells. 18 In addition, Celastrol treatment triggered heat shock response via inducing HSP70 expression.…”

Section: Introductionmentioning

confidence: 99%

Celastrol enhances Atoh1 expression in inner ear stem cells and promotes their differentiation into functional auditory neuronal-like cells

Han

Cong

et al. 2018

Organogenesis

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We aimed to investigate the beneficial effect of Celastrol on inner ear stem cells and potential therapeutic value for hearing loss. The inner ear stem cells were isolated and characterized from utricular sensory epithelium of adult mice. The stemness was evaluated by sphere formation assay. The relative expressions of Atoh1, MAP-2 and Myosin VI were measured by RT-PCR and immunoblotting. The up-regulation of MAP-2 was also analysed with immunofluorescence. The in vitro neuronal excitability was interrogated by calcium oscillation. The electrophysiological property was determined by inward current recorded on patch clamp. Our results demonstrated that Celastrol treatment significantly improved the viability and proliferation of mouse inner ear stem cells, and facilitated sphere formation. Moreover, Celastrol stimulated differentiation of mouse inner ear stem cells to neuronal-like cells and enhanced neural excitability. Celastrol also enhanced neuronal-like cell identity in the inner ear stem cell derived neurons, as well as their electrophysiological function. Most notably, these effects were apparently associated with the upregulation of Atoh1 in response to Celastrol treatment. Celastrol showed beneficial effect on inner ear stem cells and held therapeutic promise against hearing loss.

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Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators

Cited by 570 publications

References 46 publications

A novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex against pancreatic cancer cells

A novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex against pancreatic cancer cells

Targeted therapy of cancer: new roles for pathologists—prostate cancer

Celastrol enhances Atoh1 expression in inner ear stem cells and promotes their differentiation into functional auditory neuronal-like cells

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