Inhibition of Hsp90 via 17-DMAG induces apoptosis in a p53-dependent manner to prevent medulloblastoma

Ayrault, Olivier; Godeny, Michael D.; Dillon, Christopher P.; Zindy, Frédérique; Fitzgerald, Patrick; Roussel, Martine F.; Beere, Helen M.

doi:10.1073/pnas.0902880106

Cited by 30 publications

(30 citation statements)

References 40 publications

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“…Activation of macrophages and monocytes in inflammation can prevent apoptosis and lead to prolonged macrophage and monocyte viability [37,38]. Apoptosis induced by HSP90 inhibitors has shown selectivity for abnormal cells, and recently was shown to be dependent on the activation of specific apoptotic proteins [39]. The HSP90 inhibitor 17-DMAG has been shown to induce apoptosis selectively in chronic lymphoid leukemia cells [19].…”

Section: Discussionmentioning

confidence: 99%

HSP90 inhibition by 17-DMAG reduces inflammation in J774 macrophages through suppression of Akt and nuclear factor-κB pathways

et al. 2012

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Section: Discussionmentioning

confidence: 99%

HSP90 inhibition by 17-DMAG reduces inflammation in J774 macrophages through suppression of Akt and nuclear factor-κB pathways

et al. 2012

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“…14,18 In studying MBs, Ayrault et al reported that, in order for 17-DMAG to exert its antitumorigenic effect, an intact p53 response is required. 2 Apart from HSP90, an HSP70 inhibitor has also been developed and showed promise as an anticancer compound. 3 The increased expression of both HSP70 and HSP90-α in the present study suggests a possible therapeutic implication in MB.…”

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confidence: 99%

Expression of heat shock proteins in medulloblastoma

Alexiou

Vartholomatos

Stefanaki

et al. 2013

PED

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Object Medulloblastoma (MB) is the most common malignant brain tumor in children. Heat shock proteins (HSPs) comprise a superfamily of proteins that serve as molecular chaperones and are overexpressed in a wide range of human cancers. The purpose of the present study was to investigate the expression of HSP27 (pSer82), HSP27 (pSer15), HSP40, HSP60, HSP70, HSP90-α, Akt, and phospho-Akt by multiplex bead array assay of MBs. The results of HSP and Akt expression were correlated with MB subtype; immunohistochemical expression of Ki-67 index, bcl-2, and p53; and patients' prognosis. Methods The authors retrospectively evaluated 25 children with MB who underwent surgery. Immunohistochemical analysis of Ki-67, p53, and bcl-2 expression was performed in all cases. By using multiplex bead array assay, a simultaneous detection of HSP27 (pSer82), HSP27 (pSer15), HSP40, HSP60, HSP70, HSP90-α, Akt, and phospho-Akt was performed. Results Medulloblastoma with extensive nodularity had significantly lower HSP27 (pSer15) expression (p = 0.039) but significantly higher HSP60 expression (p = 0.021) than classic MB. Large-cell MB had significantly higher HSP70 expression (p = 0.028) than classic MB. No significant difference was found between HSP27 (pSer82), HSP40, HSP90-α, Akt, or phospho-Akt expression and MB subtype. Large-cell MBs had significantly higher Ki-67 index compared with classic MBs (p = 0.033). When analyzing all MBs, there was a significant negative correlation between HSP27 (pSer15) and Ki-67 index (r = −0.475, p = 0.016); a significant positive correlation between HSP70 expression and Ki-67 index (r = 0.407, p = 0.043); and a significant positive correlation between HSP70 expression and bcl-2 index (r = 0.491, p = 0.023). Patients with large-cell MB had a worse survival than those with classic MB, but the difference did not reach statistical significance (p = 0.076). Conclusions A substantial expression of several HSPs in MB was observed. Given that HSPs represent an attractive strategy for anticancer therapy, further studies, involving larger series of patients, are obviously necessary to clarify the relationship of HSPs with tumor aggressiveness and prognosis.

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“…These effects were attributed to the degradation of the Hsp90 clients, which are driver oncoproteins in these tumor types. Studies by us and other groups showed that p53 mutational status influences 17-AAG sensitivity through the effects on p53 downstream targets including PUMA, Bax, Bim, and p21 (13–15). Our recent study showed that colon cancer cells contain a small fraction (~0.1%) of pre-existing FWB7 -mutant cells, which can be enriched upon treatment with the multi-kinase inhibitor regorafenib, leading to acquired drug resistance (29).…”

Section: Discussionmentioning

confidence: 88%

“…Previous studies showed that geldanamycin and 17-AAG induce apoptosis and inhibit tumor metastasis and angiogenesis (2, 9). Several anticancer mechanisms of Hsp90 inhibitors have been proposed, such as downregulation of Akt (10), inhibition of NF-kB activation due to IKK destabilization (11), endoplasmic reticulum stress (12), and more recently, activation of p53 and its downstream targets (13–15). However, the mechanisms by which Hsp90 inhibitors selectively kill tumor cells are still not well understood.…”

Section: Introductionmentioning

confidence: 99%

FBW7-Dependent Mcl-1 Degradation Mediates the Anticancer Effect of Hsp90 Inhibitors

Tong

Tan

Nikolovska‐Coleska

et al. 2017

Molecular Cancer Therapeutics

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Heat shock protein 90 (Hsp90) is widely overexpressed in cancer cells and necessary for maintenance of malignant phenotypes. Hsp90 inhibition induces tumor cell death through degradation of its client oncoproteins, and has shown promises in preclinical studies. However, the mechanism by which Hsp90 inhibitors kill tumor cells is not well understood. Biomarkers associated with differential sensitivity and resistance to Hsp90 inhibitors remain to be identified. In this study, we found that colorectal cancer (CRC) cells containing inactivating mutations of FBW7, a tumor suppressor and E3 ubiquitin ligase, are intrinsically insensitive to Hsp90 inhibitors. The insensitive CRC cells lack degradation of Mcl-1, a pro-survival Bcl-2 family protein. Hsp90 inhibition promotes GSK3β-dependent phosphorylation of Mcl-1, which subsequently binds to FBW7 and undergoes ubiquitination and proteasomal degradation. Specifically blocking Mcl-1 phosphorylation by genetic knock-in abrogates its degradation and renders in vitro and in vivo resistance to Hsp90 inhibitors, which can be overcame by Mcl-1-selective small-molecule inhibitors. Collectively, our findings demonstrate a key role of GSK3β/FBW7-dependent Mcl-1 degradation in killing of CRC cells by Hsp90 inhibitors, and suggest FBW7 mutational status as a biomarker for Hsp90-targeted therapy.

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Inhibition of Hsp90 via 17-DMAG induces apoptosis in a p53-dependent manner to prevent medulloblastoma

Cited by 30 publications

References 40 publications

HSP90 inhibition by 17-DMAG reduces inflammation in J774 macrophages through suppression of Akt and nuclear factor-κB pathways

HSP90 inhibition by 17-DMAG reduces inflammation in J774 macrophages through suppression of Akt and nuclear factor-κB pathways

Expression of heat shock proteins in medulloblastoma

FBW7-Dependent Mcl-1 Degradation Mediates the Anticancer Effect of Hsp90 Inhibitors

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