Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
ReviewInhibition of Hsp90: a new strategy for inhibiting protein kinases
Section snippets
Introduction: chaperones and their roles in health and disease
Heat shock proteins (Hsp-s) are highly conserved ubiquitous proteins among species. They are inducible by a variety of stressors but their constitutive expression under non-stressful conditions shows their important role in the maintenance of cellular homeostasis. Hsp-s are involved in maintaining appropriate folding and conformation of other proteins, hence most of them can also be referred to “molecular chaperones”. They also help to transport proteins from one compartment to another inside
Hsp90: a chaperone with an unusual ATP-binding site, the Bergerat-fold
Hsp90 is one of the most abundant proteins in the eukaryotic cells, comprising 1–2% under non-stress conditions. It is evolutionarily conserved among species, and is proven essential for cell survival. Its contribution to various cellular processes, including signal transduction, protein folding and degradation, and morphological evolution, has been extensively studied. Hsp90 is primarily a cytosolic protein, but a small portion rapidly accumulates in cell nuclei upon stress [28], [29], [30].
Hsp90-dependent signal transduction
Over the years, many different tyrosine and serine/threonine protein kinases have been selected as potential pharmacological targets in antitumor therapies, based either on their overexpression and/or dysfunction in a particular organ or tissue, or through their association in deregulated signal transduction/cell cycle pathways. Our current understanding is that a number of distinct tyrosine kinases play a role in diverse but fundamentally important aspects of tumor progression, such as growth,
Hsp90 inhibitors
In several tumor models the selective inhibition of Hsp90 function causes a selective degradation of important signaling proteins that are involved in cell proliferation, cell cycle regulation, and apoptosis [70]. As a consequence of this, there are several Hsp90-specific drugs developed and some of them are already in clinical trials (Table 2).
Advantages of Hsp90 inhibitors
In most cases, Hsp90 inhibition has been shown to induce either cytostasis or apoptosis [87], [88]. However, there are some reports showing that, at low doses, Hsp90 inhibitors induce cell differentiation [108]. Though the differences in the downstream effects of Hsp90 inhibition leading to these various final outcomes in the fate of the cells are not known, several prominent features of Hsp90 inhibition are associated with all of these effects [109], [110], [111]. There is a selectivity of
Redox homeostasis
Oxidative stress is an imbalance between oxidant exposure and anti-oxidative protection within the cellular environment, resulting in a range of responses that depend on the cell type and on the stressor. There is cross-talk between the amount of Hsp-s and the intracellular redox homeostasis. Hsp-s, like a-crystalline, Hsp27 and Hsp70, were extensively studied for their antioxidant properties. These proteins also contribute to maintaining the intracellular redox homeostasis [117], [118]. Though
Hsp90 and the cytoarchitecture: Hsp90 inhibition leads to increased lysis of cells after hypoxia or complement attack
The eukaryotic cytoskeleton contains three major components, microfilaments, intermediate filaments, and microtubules. Extensive research in this field points to the importance of Hsp-s in stabilizing the cytoskeleton by direct interaction with cytoskeletal proteins [120], [121]. The growing list of Hsp90-interacting cytoskeletal proteins suggests that Hsp90 plays a major role in preserving these structures, hence it is involved in maintaining the cell shape. It was also proposed that apart
Limitations of anti-Hsp90 drugs
Though Hsp90 inhibitors exhibit selective effects in inducing the degradation of Hsp90 client proteins, they are also associated with other effects unrelated to their binding to Hsp90. Geldanamycin, which contains a quinone group, is known to induce reactive oxygen species, and in general, the cytotoxicity of the ansamycin antibiotics has been attributed to free radical generation [126], [127], [128], [129]. Radicicol is also involved in free-radical formation from non-peroxide compounds [130],
Conclusions and perspectives
The word “cancer” can be regarded as a gross term for a vast number of many different disease conditions with distinct characteristics and therapeutic requirements. Though the general features of cancer include unrestrained cell proliferation, a great variety of mutations as well as deregulation of numerous genes can cause this. Among the hallmarks of cancer [132], up-regulation of growth signals and evasion of apoptosis are the most important. As most growth regulatory signals depend on Hsp90
Acknowledgements
Work in the authors' laboratory was supported by research grants from the EU 6th Framework program (FP6506850), from the Hungarian Science Foundation (OTKA-T37357), from the Hungarian Ministry of Social Welfare (ETT-32/03) from the International Centre for Genetic Engineering and Biotechnology (ICGEB, CRP/HUN 99-02). A.S.S. is a recipient of National Overseas Scholarship from Ministry of Social Justice and Empowerment, Government of India.
References (132)
- et al.
The Hsp70 and Hsp60 chaperone machines
Cell
(1998) - et al.
GRP94, an ER chaperone with protein and peptide binding properties
Semin. Cell Dev. Biol.
(1999) A platform for compartmentalized protein synthesis: protein translation and translocation in the ER
Curr. Opin. Cell Biol.
(2002)- et al.
Heat shock proteins come of age: primitive functions acquire new roles in an adaptive world
Immunity
(1998) Escaping cell death: survival proteins in cancer
Exp. Cell Res.
(1999)- et al.
Protein folding in vivo: unraveling complex pathways
Cell
(1997) Hsp90 inhibitors as novel cancer chemotherapeutic agents
Trends Mol. Med.
(2002)- et al.
The 90-kDa molecular chaperone family: structure, function, and clinical applications. A comprehensive review
Pharmacol. Ther.
(1998) Hsp90 & Co.-a holding for folding
Trends Biochem. Sci.
(1999)- et al.
In vitro evidence that hsp90 contains two independent chaperone sites
FEBS Lett.
(1997)
Chick heat-shock protein of Mr=90,000, free or released from progesterone receptor, is in a dimeric form
J. Biol. Chem.
Analysis of native forms and isoform compositions of the mouse 90-kDa heat shock protein, HSP90
J. Biol. Chem.
Localization and characterization of the 86- and 84-kDa heat shock proteins in Hepa 1c1c7 cells
Exp. Cell Res.
Characterization of purified avian 90,000-Da heat shock protein
Arch. Biochem. Biophys.
Structure, function, and mechanism of the Hsp90 molecular chaperone
Adv. Protein Chem.
The heat shock protein 90 antagonist novobiocin interacts with a previously unrecognized ATP-binding domain in the carboxyl terminus of the chaperone
J. Biol. Chem.
A nucleotide-dependent molecular switch controls ATP binding at the C-terminal domain of Hsp90. N-terminal nucleotide binding unmasks a C-terminal binding pocket
J. Biol. Chem.
Binding of ATP to heat shock protein 90: evidence for an ATP-binding site in the C-terminal domain
J. Biol. Chem.
The Hsp90 complex–a super-chaperone machine as a novel drug target
Biochem. Pharmacol.
Folding of the glucocorticoid receptor by the heat shock protein (hsp) 90-based chaperone machinery. The role of p23 is to stabilize receptor.hsp90 heterocomplexes formed by hsp90.p60.hsp70
J. Biol. Chem.
Hop as an adaptor in the heat shock protein 70 (Hsp70) and hsp90 chaperone machinery
J. Biol. Chem.
A model for the cytoplasmic trafficking of signalling proteins involving the hsp90-binding immunophilins and p50cdc37
Cell Signal.
BCR-ABL point mutants isolated from patients with imatinib mesylate-resistant chronic myeloid leukemia remain sensitive to inhibitors of the BCR-ABL chaperone heat shock protein 90
Blood
HGF: a multifunctional growth factor controlling cell scattering
Int. J. Biochem. Cell Biol.
Disruption of the Raf-1-Hsp90 molecular complex results in destabilization of Raf-1 and loss of Raf-1-Ras association
J. Biol. Chem.
The 90-kDa heat shock protein, HSP90, binds and protects casein kinase II from self-aggregation and enhances its kinase activity
J. Biol. Chem.
Evidence for the association of the heme-regulated eIF-2 alpha kinase with the 90-kDa heat shock protein in rabbit reticulocyte lysate in situ
J. Biol. Chem.
Requirement for a kinase-specific chaperone pathway in the production of a Cdk9/cyclin T1 heterodimer responsible for P-TEFb-mediated tat stimulation of HIV-1 transcription
J. Biol. Chem.
Hypoxia-induced activation of HIF-1: role of HIF-1alpha-Hsp90 interaction
FEBS Lett.
Geldanamycin-induced destabilization of Raf-1 involves the proteasome
Biochem. Biophys. Res. Commun.
Crystal structure of an Hsp90-geldanamycin complex: targeting of a protein chaperone by an antitumor agent
Cell
p185erbB2 binds to GRP94 in vivo. Dissociation of the p185erbB2/GRP94 heterocomplex by benzoquinone ansamycins precedes depletion of p185erbB2
J. Biol. Chem.
Synthesis and evaluation of geldanamycin–testosterone hybrids
Bioorg. Med. Chem. Lett.
Synthesis and evaluation of geldanamycin–estradiol hybrids
Bioorg. Med. Chem. Lett.
LY294002-geldanamycin heterodimers as selective inhibitors of the PI3K and PI3K-related family
Bioorg. Med. Chem. Lett.
Disruption of HSP90 function reverts tumor necrosis factor-induced necrosis to apoptosis
J. Biol. Chem.
Radicicol-sensitive peptide binding to the N-terminal portion of GRP94
J. Biol. Chem.
Halohydrin and oxime derivatives of radicicol: synthesis and antitumor activities
Bioorg. Med. Chem.
Molecular chaperones in cellular protein folding
Nature
Molecular chaperones in the cytosol: from nascent chain to folded protein
Science
Protein import into mitochondria
Annu. Rev. Biochem.
Programmed cell death: many ways for cells to die decently
Ann. Med.
Linking gene expression patterns to therapeutic groups in breast cancer
Cancer Res.
Do heat shock proteins have a role in breast cancer?
Br. J. Cancer
Prognostic significance of heat shock proteins 27 and 70 in patients with squamous cell carcinoma of the esophagus
Cancer
Clinical and biological significance of HSP89 alpha in human breast cancer
Int. J. Cancer
Unusual expression and localization of heat-shock proteins in human tumor cells
Int. J. Cancer
Constitutive overexpression of a 89 kDa heat shock protein gene in the HBL100 human mammary cell line converted to a tumorigenic phenotype by the EJ/T24 Harvey-ras oncogene
Oncogene
alpha-Synuclein shares physical and functional homology with 14-3-3 proteins
J. Neurosci.
Bacterial and yeast chaperones reduce both aggregate formation and cell death in mammalian cell models of Huntington's disease
Proc. Natl. Acad. Sci. U. S. A.
Cited by (134)
Mitochondria in biology and medicine – 2023
2024, MitochondrionThe conformation-specific Hsp90 inhibition interferes with the oncogenic RAF kinase adaptation and triggers premature cellular senescence, hence, acts as a tumor suppressor mechanism
2021, Biochimica et Biophysica Acta - Molecular Cell ResearchHsp90 chaperone facilitates E2F1/2-dependent gene transcription in human breast cancer cells
2021, European Journal of Cell BiologyCitation Excerpt :Hsp90 promotes proliferation by stabilizing the functions of mutated oncogenic products (Csermely et al. (1998); Pratt (1998); Whitesell and Lindquist (2005)). Further, Hsp90 is shown to be in the center of cellular folding machinery as well in the signaling networks (Csermely et al. (1998); Sreedhar et al. (2004)). The acquired high-affinity conformation of Hsp90 is involved in these tumor-selective functions (Kamal et al., 2003).
Hsp90 regulates HDAC3-dependent gene transcription while HDAC3 regulates the functions of Hsp90
2020, Cellular Signalling
- 1
On leave from Centre for Cellular and Molecular Biology, Hyderabad, 500 007, India.