Review
Inhibition of Hsp90: a new strategy for inhibiting protein kinases

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Abstract

The 90-kDa heat shock protein (Hsp90) is a ubiquitous, evolutionarily highly conserved, molecular chaperone in the eukaryotic cytosol. Hsp90, together with a number of other chaperones, promotes the conformational maturation of a large variety of protein kinases. Inhibition of Hsp90 function results in the collapse of the metastable conformation of most of these kinases and leads to their proteolytic elimination by the proteasome. Numerous natural and synthetic Hsp90 inhibitors have been developed in recent years. Some of these inhibitors are also involved in sensitizing tumor cells to pro-apoptotic insults, hence serve as anti-cancer drugs. Here we review these novel protein kinase inhibitors and their emerging role in various cellular processes, apart from their inhibition of Hsp90 protein function. We focus not only on Hsp90-tumor progression, but also on cytoarchitecture, as the higher levels of cellular organization need constant remodeling, where the role of Hsp90 requires investigation. Our last major aspect deals with protein oxidation, since several Hsp90 inhibitors exert pro-oxidant effects.

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.

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    On leave from Centre for Cellular and Molecular Biology, Hyderabad, 500 007, India.

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