Targeting heat shock protein 72 enhances Hsp90 inhibitor-induced apoptosis in myeloma

Davenport, Emma L.; Zeisig, Athanasia; Aronson, Lauren I.; Moore, Hannah E.; Hockley, Sarah L.; González, David; Smith, Emma; Powers, Marissa; Sharp, Swee Y.; Workman, Paul; Morgan, Gareth J.; Davies, Faith E.

doi:10.1038/leu.2010.168

Cited by 71 publications

(70 citation statements)

References 9 publications

(10 reference statements)

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“…40,87,88 Indeed, HSP90 inhibitors have, in general, performed poorly as single agents for the treatment of multiple myeloma in the clinic. 134 highlighting the need to look at these compensatory mechanisms in order to enhance apoptosis of myeloma cells.…”

Section: Discussionmentioning

confidence: 99%

“…Activity was mirrored in vivo where, in addition, it significantly prolonged survival. 87 However, 17-AAG also induces the UPR, 40 and HSP70 is up-regulated in response to HSP90 inhibition, 88 suggesting that in order to achieve an optimal clinical response with HSP90 inhibitors, they should be used in a combination approach. To this end, 17-AAG or its analog 17-DMAG, in combination with either of the PI3K pathway inhibitors, perifosine or rapamycin, demonstrated synergistic cytotoxicity in myeloma cells, inhibited angiogenesis, and was able to overcome the protective effects of the bone marrow microenvironment.…”

Section: Heat-shock Chaperone Inhibitorsmentioning

confidence: 99%

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DangER: protein ovERload. Targeting protein degradation to treat myeloma

Aronson¹,

Davies²

2012

Haematologica

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Myeloma is a malignancy of the antibody-producing plasma cells and, as such, these cells synthesize large quantities of unfolded or misfolded immunoglobulin. The build-up of excess protein triggers a number of downstream signal transduction cascades, including endoplasmic reticulum stress and autophagy. As a result, myeloma cells are uniquely reliant on these and other protein handling pathways for their survival. Strategies aimed at targeting this vulnerability have proved successful with the proteasome inhibitor, bortezomib, already licensed for clinical use. In addition to the proteasome, various other points within the protein handling pathways are also the subject of drug discovery projects, with some already progressing into clinical trials. These include compounds directed against heat shock proteins, the unfolded protein response and pathways both upstream and downstream of the proteasome.More recently, the role of autophagy has been recognized in myeloma. In this review, we discuss the various pathways used by myeloma cells for survival, with particular emphasis on the emerging role and conundrum of autophagy, as well as highlighting pre-clinical research on novel inhibitors targeting protein handling pathways.Key words: autophagy, proteasome, ER stress, heat-shock chaperones, unfolded protein response.Citation: Aronson LI and Davies FE. DangER: protein ovERload. Targeting protein degradation to treat myeloma. Haematologica 2012;97(8):1119-1130. doi:10.3324/haematol.2012 This is an open-access paper. ABSTRACT © F e r r a t a S t o r t i F o u n d a t i o nbeen extensively reviewed and so will not be covered further here. 7,8 We aim to provide an overview of the protein handling and stress response pathways. We highlight the potential points in these pathways that can be targeted therapeutically, and review the supporting pre-clinical data. Protein handling pathwaysUnder normal conditions, the synthesis, folding and degradation of cellular proteins are balanced processes. In myeloma cells, however, the protein folding capacity of the endoplasmic reticulum (ER) is overloaded by large quantities of immunoglobulin and cells must adapt to this continual stress. 9 A close relationship with common signaling nodes therefore exists between the ubiquitin proteasome pathway, cellular stress pathways such as the unfolded protein response (UPR), heat shock response and autophagy. Ubiquitin proteasome pathwayThe main cellular pathway for the removal and destruction of proteins is the ubiquitin proteasome pathway. This involves the sequential enzymatic transfer of ubiquitin monomers onto an elongating polyubiquitin chain bound at the lysine 11 or lysine 48 residues of target proteins. 10 In the first step of this cascade, an E1 activating enzyme, typically ubiquitin activating enzyme (UAE, also known as UBA1), binds ubiquitin. A second ubiquitin monomer binds to a different site on the E1 enzyme and the first ubiquitin is transferred to an E2 ubiquitin-conjugating enzyme. The final step involves the transfer of ubiq...

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Section: Discussionmentioning

confidence: 99%

Section: Heat-shock Chaperone Inhibitorsmentioning

confidence: 99%

DangER: protein ovERload. Targeting protein degradation to treat myeloma

Aronson¹,

Davies²

2012

Haematologica

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“…14 Interestingly, a strong upregulation of Hsp72 has been reported after pharmacological Hsp90 inhibition, also in MM cells. 10,11,15 Furthermore, it has recently been shown that dual silencing of Hsp72 and Hsp73 in cell lines derived from solid tumors led to degradation of Hsp90 client proteins and to tumor-specific growth inhibition. 16 Taken together these data suggest that Hsp72 and Hsp73 may mitigate Hsp90 blockade-mediated cytotoxicity in cancer cells, and thus contribute to drug resistance.…”

Section: Introductionmentioning

confidence: 99%