Hsp90: the vulnerable chaperone

Chiosis, Gabriela; Vilenchik, Maria; Kim, Joungnam; Solit, David B.

doi:10.1016/s1359-6446(04)03245-3

Cited by 212 publications

(202 citation statements)

References 45 publications

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“…The chaperoning function of Hsp90 can be 'switchedoff' by inhibiting its ATPase activity (Chiosis et al, 2004;Dymock et al, 2004) and indeed, most current Hsp90 inhibitors act by binding to the ATP pocket in the N-terminal domain of the protein. Although other inhibitory mechanism are currently under exploration (for example, interference with cochaperone binding and function in the so-called superchaperone complex or binding to the C-terminal nucleotide binding site), this section is focused on the compounds targeting the Nterminal ATP binding cleft (for a recent review on this topic, see Bishop et al, 2007).…”

Section: Phospholipids-antagonists Of Ph Domainsmentioning

confidence: 99%

Drug discovery approaches targeting the PI3K/Akt pathway in cancer

2008

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Section: Phospholipids-antagonists Of Ph Domainsmentioning

confidence: 99%

Drug discovery approaches targeting the PI3K/Akt pathway in cancer

2008

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“…Possible factors responsible for Hsp90 modification include its specific interaction with co-chaperones (24,36) and/or alterations in the post-translational state of Hsp90, co-chaperones, or both (49).…”

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Tumor Selectivity of Hsp90 Inhibitors: The Explanation Remains Elusive

2006

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“…Although HSPs are expressed in normal cells, they are frequently overexpressed in cancer cells, suggesting a role in maintaining the malignant transformation (3,11,12). HSP90 is the most abundant protein in eukaryotic cells and it selectively interacts with and stabilizes several key signaling proteins, protein kinases, and oncogenic signal transduction proteins, making it an attractive target for cancer therapy (5,6,13,14).…”

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confidence: 99%

Inhibition of Heat Shock Protein 90 Function by 17-Allylamino-17-Demethoxy-Geldanamycin in Hodgkin's Lymphoma Cells Down-Regulates Akt Kinase, Dephosphorylates Extracellular Signal–Regulated Kinase, and Induces Cell Cycle Arrest and Cell Death

Georgakis¹,

Yang²,

Rassidakis

et al. 2006

Clinical Cancer Research

114

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Purpose: Heat shock protein 90 (HSP90) is a chaperone for several client proteins involved in transcriptional regulation, signal transduction, and cell cycle control. HSP90 is abundantly expressed by a variety of tumor types and has been recently targeted for cancer therapy. The objective of this study was to determine the role of HSP90 in promoting growth and survival of Hodgkin's lymphoma and to determine the molecular consequences of inhibiting HSP90 function by the small-molecule 17-allylamino-17-demethoxy-geldanamycin (17-AAG) in Hodgkin's lymphoma. Experimental Design: HSP90 expression in Hodgkin's lymphoma cell lines was determined by Western blot and in primary lymph node sections from patients with Hodgkin's lymphoma by immunohistochemistry. Cell viability was determined by the 3-(4,5-dimethyl-thiazol-2yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. Apoptosis and cell cycle fractions were determined by flow cytometry. Expression of intracellular proteins was determined by Western blot. Results: HSP90 is overexpressed in primary and cultured Hodgkin's lymphoma cells. Inhibition of HSP90 function by 17-AAG showed a time-and dose-dependent growth inhibition of Hodgkin's lymphoma cell lines.17-AAG induced cell cycle arrest and apoptosis, which were associated with a decrease in cyclin-dependent kinase (CDK) 4, CDK 6, and polo-like kinase1 (PLK1), and induced apoptosis by caspase-dependent and caspase-independent mechanisms. Furthermore, 17-AAG depleted cellular contents of Akt, decreased extracellular signal^regulated kinase (ERK) phosphorylation, and reduced cellular FLICE-like inhibitory protein levels (FLIP), and thus enhanced the cytotoxic effect of doxorubicin and agonistic anti^tumor necrosis factor^related apoptosisinducing ligand (TRAIL) death receptor antibodies. Conclusion: Inhibition of HSP90 function induces cell death and enhances the activity of chemotherapy and anti^tumor necrosis factor^related apoptosis-inducing ligand death receptor antibodies, suggesting that targeting HSP90 function might be of therapeutic value in Hodgkin's lymphoma.

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Hsp90: the vulnerable chaperone

Cited by 212 publications

References 45 publications

Drug discovery approaches targeting the PI3K/Akt pathway in cancer

Drug discovery approaches targeting the PI3K/Akt pathway in cancer

Tumor Selectivity of Hsp90 Inhibitors: The Explanation Remains Elusive

Inhibition of Heat Shock Protein 90 Function by 17-Allylamino-17-Demethoxy-Geldanamycin in Hodgkin's Lymphoma Cells Down-Regulates Akt Kinase, Dephosphorylates Extracellular Signal–Regulated Kinase, and Induces Cell Cycle Arrest and Cell Death

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