Chemical Tools to Investigate Mechanisms Associated with HSP90 and HSP70 in Disease

Shrestha, Liza; Patel, Hardik J.; Chiosis, Gabriela

doi:10.1016/j.chembiol.2015.12.006

Cited by 66 publications

(70 citation statements)

References 113 publications

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“…Toxicity to HSP90 inhibition correlated with the presence of the epichaperome ( P = 0.0006; R 2 = 0.71) but was independent of the levels of chaperome members, HSP90 client proteins, anti-apoptotic proteins and genetic alterations. This correlation held in over 90 cell lines encompassing breast cancer, lung cancer, pancreatic and gastric cancers, leukaemia and lymphomas ( P < 0.0001; R 2 = 0.44) and was true for several HSP90 inhibitors 19,20 (Extended Data Fig. 10).…”

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confidence: 84%

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The epichaperome is an integrated chaperome network that facilitates tumour survival

Rodina

Wang

Yan

et al. 2016

Nature

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Transient, multi-protein complexes are important facilitators of cellular functions. This includes the chaperome, an abundant protein family comprising chaperones, co-chaperones, adaptors, and folding enzymes—dynamic complexes of which regulate cellular homeostasis together with the protein degradation machinery1–6. Numerous studies have addressed the role of chaperome members in isolation, yet little is known about their relationships regarding how they interact and function together in malignancy7–17. As function is probably highly dependent on endogenous conditions found in native tumours, chaperomes have resisted investigation, mainly due to the limitations of methods needed to disrupt or engineer the cellular environment to facilitate analysis. Such limitations have led to a bottleneck in our understanding of chaperome-related disease biology and in the development of chaperome-targeted cancer treatment. Here we examined the chaperome complexes in a large set of tumour specimens. The methods used maintained the endogenous native state of tumours and we exploited this to investigate the molecular characteristics and composition of the chaperome in cancer, the molecular factors that drive chaperome networks to crosstalk in tumours, the distinguishing factors of the chaperome in tumours sensitive to pharmacologic inhibition, and the characteristics of tumours that may benefit from chaperome therapy. We find that under conditions of stress, such as malignant transformation fuelled by MYC, the chaperome becomes biochemically ‘rewired’ to form a network of stable, survival-facilitating, high-molecular-weight complexes. The chaperones heat shock protein 90 (HSP90) and heat shock cognate protein 70 (HSC70) are nucleating sites for these physically and functionally integrated complexes. The results indicate that these tightly integrated chaperome units, here termed the epichaperome, can function as a network to enhance cellular survival, irrespective of tissue of origin or genetic background. The epichaperome, present in over half of all cancers tested, has implications for diagnostics and also provides potential vulnerability as a target for drug intervention.

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confidence: 84%

“…We found that PU-H71, an HSP90 inhibitor that binds to HSP90 more strongly when HSP90 is complexed with co-chaperones and onco-client proteins 7,18,19 , also bound HSP90 more tightly in type 1 than in type 2 cells (Extended Data Fig. 3a–j).…”

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confidence: 91%

The epichaperome is an integrated chaperome network that facilitates tumour survival

Rodina

Wang

Yan

et al. 2016

Nature

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221

531

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“…chemical probes, have been used to probe HSP90 function in a number of studies (reviewed by Shrestha et al [35]). Most often, they are used not only to inhibit HSP90 activity but they can also serve as capturing agents.…”

Section: Hsp90 Interactomicsmentioning

confidence: 99%

“…An improvement in the identified interactomes came upon the use of immobilized inhibitors that enrich in the active, client-protein bound, HSP90 (Figure 1(d)). One such inhibitor is PU-H71, and chemical probes using immobilized PU-H71 have been used in a variety of cancer interactome investigations, both in non-biased, MS-based inquiries [14,15,36–38], and in biased, interactome validation studies by Western blot [35,39–42], as we detail below.…”

Section: Hsp90 Interactomicsmentioning

confidence: 99%

Proteomic interrogation of HSP90 and insights for medical research

Weidenauer

Wang

Joshi

et al. 2017

Expert Review of Proteomics

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Introduction Heat shock protein 90 (HSP90) regulates protein homeostasis in eukaryotes. As a ‘professional interactor’, HSP90 binds to and chaperones many proteins and has both housekeeping and disease-related functions but its regulation remains in part elusive. HSP90 complexes are a target for therapy, notably against cancer, and several inhibitors are currently in clinical trials. Proteomic studies have revealed the vast interaction network of HSP90 and, in doing so, the extent of cellular processes the chaperone takes part in, especially in yeast and human cells. Furthermore, small-molecule inhibitors were used to probe the global impact of its inhibition on the proteome. Areas covered We review here recent HSP90-related interactomics and total proteome studies and their relevance for research on cancer, neurodegenerative and pathogen diseases. Expert commentary Proteomics experiments are our best chance to identify the context-dependent global proteome of HSP90 and thus uncover and understand its disease-specific biology. However, understanding the complexity of HSP90 will require multiple complementary, quantitative approaches and novel bioinformatics to translate interactions into ordered functional networks and pathways. Developing therapies will necessitate more knowledge on HSP90 complexes and networks with disease relevance and on total proteome changes induced by their perturbation. Most work has been done in cancer, thus a lot remains to be done in the context of other diseases.

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“…To address this question we also employed a variety of novel tools and methods; these maintained the endogenous native state of tumors and thus queried the chaperome in its natural state [5-8]. …”

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confidence: 99%