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

Georgakis, Georgios V.; Yang, Li; Rassidakis, Georgios Z.; Martinez‐Valdez, Héctor; Medeiros, L. Jeffrey; Younes, Anas

doi:10.1158/1078-0432.ccr-05-1194

Cited by 114 publications

(117 citation statements)

References 48 publications

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“…Such a notion is supported by our observation that transient overexpression of NF-kB p65 efficiently protected L540Cy cells from geldanamycin-induced cell death. Our experiments confirm observations by Georgakis et al, 25 who described Figure 4 Treatment of HRS cells with nutlin-3(a) in addition to chemotherapeutic agents strongly enhances apoptotic effects. Wild-type TP53 cells were exposed for 5 days to low concentrations of the conventional cytotoxic drugs doxorubicin (Dox), etoposide (Eto) or vincristine (Vin), with low concentrations of nutlin-3a (or nutlin-3 in the case of L591) added for the last 3 days.…”

Section: Apoptosis Induction In Hodgkin Cellssupporting

confidence: 91%

Pharmacologic activation of p53-dependent and p53-independent apoptotic pathways in Hodgkin/Reed-Sternberg cells

et al. 2007

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The status of the p53 pathway in classical Hodgkin lymphoma (cHL) remains unclear, and a lack of proven TP53 mutations contrasts with often high expression levels of p53 protein. In this study, we demonstrate that pharmacologic activation of the p53 pathway with the murine double minute 2 (MDM2) antagonist nutlin-3 in Hodgkin lymphoma-derived cell lines leads to effective apoptosis induction and sensitizes the cells to other anticancer drugs. Cells with mutant p53 are resistant to nutlin-3, but sensitive to geldanamycin, a pharmacologic inhibitor of heat shock 90 kDa protein (HSP90), indicating that HSP90 inhibition can induce apoptosis in a p53-independent manner. Conversely, cells with defects in the HSP90/nuclear factor-j B pathway expressing wild-type p53 are more resistant to geldanamycin, but still sensitive to nutlin-3. Our results suggest that selective activation of p53 by MDM2 antagonists as a single agent or in combination with conventional chemotherapeutics and/or inhibitors of p53-independent survival pathways may offer effective treatment options for patients with cHL. Importantly, because nutlins and HSP90 inhibitors are non-genotoxic agents, their use might offer a means to reduce the genotoxic burden of current chemotherapeutic regimens.

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Section: Apoptosis Induction In Hodgkin Cellssupporting

confidence: 91%

Pharmacologic activation of p53-dependent and p53-independent apoptotic pathways in Hodgkin/Reed-Sternberg cells

et al. 2007

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“…Up-regulation of cyclin B1 and prolonged activation of cyclin B1/Cdc2 complex are typical features of mitotic catastrophe (25). It has been described previously that other cell cycle regulators such as Aurora B, survivin, and Plk1 are client proteins of Hsp90 (23,24). According to our data neither Aurora B, survivin, nor Plk1 were affected after 17-AAG.…”

Section: Discussionsupporting

confidence: 52%

Mitotic catastrophe cell death induced by heat shock protein 90 inhibitor in BRCA1-deficient breast cancer cell lines

Zając¹,

Moneo

Carnero

et al. 2008

Molecular Cancer Therapeutics

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Heat shock protein 90 (Hsp90) is a molecular chaperone involved in folding, assembly, maturation, and stabilization of the client proteins that regulate survival of malignant cells. As previous reports correlate high Hsp90 expression with decreased survival in breast cancer, Hsp90 may be a favorable target for investigational therapy in breast cancer. In our study, we have examined the response of a panel of both BRCA1-null (UACC 3199, HCC 1937, and MBA-MD-436) and BRCA1-wt breast cancer cell lines (MCF-7, MBA-MD-157, and Hs578T) to determine the proteins governing response to Hsp90 inhibitor 17-allyloamino-17-demethoxy-geldanamycin. On treatment with the drug, cells arrested at G 2 -M phase and entered aberrant mitosis in a BRCA1-dependent manner. Failure to arrest the cells at or before mitosis resulted in formation of micronucleated cells, aberrant segregation of chromosomes, microtubule misalignment, and multicentrosomes, leading in eventual mitotic catastrophe cell death. Our observations show that BRCA1 mediates G 2 -M transition mainly through chek1 on 17-allyloamino-17-demethoxy-geldanamycin treatment.

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“…Hsp90 inhibitors, such as geldanamycin, 17-allylamino-17-demethoxygeldanamycin (17AAG) and radicicol, have been shown to potentiate tumor cell killing induced by distinct antitumor agents by inhibiting survival signaling (Whitesell and Lindquist, 2005). However, we found that the above Hsp90 inhibitors, within the concentration range used in preclinical studies (Georgakis et al, 2006), diminished significantly in a dose-dependent manner the apoptotic response induced by EDLF in leukemic cells (Figures 2a and b). These results suggest an unexpected role of Hsp90 in the induction of apoptosis in EDLF-treated leukemic cells, a rather different view from the previously assumed role of Hsp90 in potentiating survival.…”

Section: Resultsmentioning

confidence: 86%

Proapoptotic role of Hsp90 by its interaction with c-Jun N-terminal kinase in lipid rafts in edelfosine-mediated antileukemic therapy

et al. 2007

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Heat shock protein 90 (Hsp90) is a survival signaling chaperone and a cancer chemotherapeutic target. However, we have found that inhibitors of Hsp90 diminished the apoptotic response induced in leukemic cells by the antitumor alkyl-lysophospholipid analog edelfosine, which acts through lipid raft reorganization. Edelfosine treatment recruited Hsp90, c-Jun N-terminal kinase (JNK) and apoptotic molecules in lipid rafts, but not the JNK regulators apoptosis signal-regulating kinase 1 (ASK1) and Daxx, or the survival signaling molecules extracellular signal-regulated kinase (ERK) and Akt. Following edelfosine treatment, Hsp90 bound to JNK in lipid rafts and Hsp90-JNK clusters were identified at the plasma membrane by immunoelectron microscopy. Hsp90 inhibition reduced JNK protein level in lipid rafts and turned proapoptotic persistent JNK activation into a transient response in edelfosine-treated cells. Decrease in edelfosine-induced JNK activation and apoptosis by Hsp90 inhibition was prevented through proteasome inhibition, suggesting that Hsp90 inhibition diminishes apoptosis by promoting JNK protein degradation. Expression of ASK1 dominant negative mutant did not affect JNK activation and apoptosis following edelfosine treatment. These data indicate that lipid raft-recruited JNK is ASK1-independent and becomes a novel Hsp90 client protein. Our results reveal a new chaperoning role of Hsp90 on JNKmediated apoptosis following its recruitment in lipid rafts.

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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

Cited by 114 publications

References 48 publications

Pharmacologic activation of p53-dependent and p53-independent apoptotic pathways in Hodgkin/Reed-Sternberg cells

Pharmacologic activation of p53-dependent and p53-independent apoptotic pathways in Hodgkin/Reed-Sternberg cells

Mitotic catastrophe cell death induced by heat shock protein 90 inhibitor in BRCA1-deficient breast cancer cell lines

Proapoptotic role of Hsp90 by its interaction with c-Jun N-terminal kinase in lipid rafts in edelfosine-mediated antileukemic therapy

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