Key Points
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Most heat-shock proteins (HSPs) are constitutively expressed molecular chaperones that guide the normal folding, intracellular disposition and proteolytic turnover of many of the key regulators of cell growth and survival. Their levels of intracellular expression increase in response to protein-denaturing stressors, such as temperature change, as an evolutionarily conserved response to restore the normal protein-folding environment and to enhance cell survival.
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The essential chaperoning functions of HSPs are subverted during oncogenesis to make malignant transformation possible and to facilitate rapid somatic evolution.
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Functioning as biochemical buffers for the numerous genetic lesions that are present within tumours, chaperones, especially HSP90, allow mutant proteins to retain or even gain function while permitting cancer cells to tolerate the imbalanced signalling that such oncoproteins create.
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Highly specific inhibitors of HSP90 have been identified that redirect its chaperoning activity and decrease cellular levels of the many cancer-related client proteins that depend on it for their function.
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The use of HSP90 inhibitors has proven invaluable at a basic level in probing the complex cellular functions of this chaperone.
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The modulation of client protein levels has been demonstrated in animal models and cancer patients following systemically well-tolerated exposure to the HSP90 inhibitor 17AAG, which is the first in its class.
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Work is ongoing to identify and develop new HSP90 inhibitors with improved pharmacological properties.
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The best way to exploit the novel mechanism of action of HSP90 inhibitors for anticancer therapy remains to be defined, but probably involves combination with conventional cytotoxic drugs or other molecularly targeted agents.
Abstract
Standing watch over the proteome, molecular chaperones are an ancient and evolutionarily conserved class of proteins that guide the normal folding, intracellular disposition and proteolytic turnover of many of the key regulators of cell growth, differentiation and survival. This essential guardian function is subverted during oncogenesis to allow malignant transformation and to facilitate rapid somatic evolution. Pharmacologically 'bribing' the essential guard duty of the chaperone HSP90 (heat-shock protein of 90 kDa) seems to offer a unique anticancer strategy of considerable promise.
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DATABASES
Entrez Gene
National Cancer Institute
FURTHER INFORMATION
Annotated summary of known HSP90 client proteins
Glossary
- CHAPERONE
-
A class of proteins that prevent improper associations and assist in the correct folding and maturation of other cellular proteins collectively termed clients and substrates. In most cases, chaperones do not participate in the final mature structures that their clients form.
- GELDANAMYCIN
-
Natural-product antibiotic of the benzoquinone ansamycin class that inhibits the chaperone activity of HSP90.
- CANALIZATION
-
The funnelling of variation into discrete, well-defined outcomes, especially during developmental processes.
- RADICICOL
-
Natural-product antibiotic of the macrolide class that inhibits the chaperone activity of HSP90.
- ISOMERIZATION
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A change in the structural organization of a compound without altering its underlying chemical composition.
- DAUER DEVELOPMENTAL ARREST
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An alternate third stage of larval development in C. elegans that enhances survival of the organism under harsh conditions.
- FORWARD CHEMICAL-GENETIC APPROACH
-
The use of small-molecule chemical libraries to generate phenotypes of interest in a manner analogous to mutagenesis in classical genetic screens. Any active compounds found can be used to identify the proteins involved in regulating biological processes, to provide molecular insights into how specific proteins perform their biological functions and to identify lead compounds for the development of useful therapeutics.
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Whitesell, L., Lindquist, S. HSP90 and the chaperoning of cancer. Nat Rev Cancer 5, 761–772 (2005). https://doi.org/10.1038/nrc1716
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DOI: https://doi.org/10.1038/nrc1716
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