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Inhibition of Cancer Invasion and Metastasis by Targeting the Molecular Chaperone Heat-Shock Protein 90

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Inhibition of Cancer Invasion and Metastasis by Targeting the Molecular Chaperone Heat-Shock Protein 90 ANTICANCER RESEARCH 29: 797-808 (2009) Review Inhibition of Cancer Invasion and Metastasis by Targeting the Molecular Chaperone Heat-shock Protein 90 FUMITAKA KOGA1, KAZUNORI KIHARA1 and LEN NECKERS2 1Department of Urology, Tokyo Medical and Dental University Graduate School, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan; 2Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, U.S.A. Abstract. Heat-shock protein 90 (Hsp90) is a molecular strategies have made their way from the bench to the patient, chaperone required for the stability and function of numerous and are now used as part of the standard clinical modalities oncogenic signaling proteins that determine the hallmarks of available against a variety of malignancies. cancer. Receptor tyrosine kinases (RTKs) and hypoxia-inducible Heat-shock protein 90 (Hsp90) is a molecular chaperone factor-1 (HIF-1)-mediated pathways, commonly activated in required for the stability and function of conditionally aggressive cancer, potentiate each other and thus efficiently activated signaling proteins as well as multiple mutated, promote cancer invasion and metastasis. Hsp90 inhibitors, by chimeric and/or overexpressed signaling proteins, which interacting specifically with a single molecule, Hsp90, cause the promote cancer cell growth and survival (1, 2). Its role in destabilization and eventual degradation of multiple Hsp90 client cancer has received much attention in the past decade since proteins. These agents impede the cellular processes involved in Hsp90 functions as an integral part of the machinery that cancer invasion and metastasis by simultaneously impairing allows cancer cells to escape normal regulation. Several multiple Hsp90-dependent signaling proteins including HIF-1α, selective Hsp90 inhibitors are currently undergoing clinical most RTKs and their hub mediators Src, Raf-1 and Akt. Recently, evaluation. This review focuses on the role of Hsp90 in a fraction of Hsp90 identified on the cell surface has been found cancer invasion and angiogenesis, the crucial steps for the to play a crucial role in cancer invasion and metastasis. The development of cancer metastasis, and discusses the potential first-in-class Hsp90 inhibitor, 17-allylamino-17-demethoxy- utility and problems of Hsp90 inhibitors in clinical settings. geldanamycin, is currently in phase II clinical trials. The potential utility and problems of Hsp90 inhibitors in clinical Physiological Role of Hsp90 settings are discussed. A fuller understanding of the roles of as a Molecular Chaperone Hsp90 in cancer biology and accumulating clinical data on Hsp90 inhibitors will guide us toward the goal of optimizing the Hsp90 is an extremely abundant chaperone protein, use of these agents in the clinic. comprising up to 1 to 2% of total cellular protein. It increases by 2- to 10-fold during environmental stress; this Accumulating evidence on molecular pathways in cancer up-regulation could be explained as a part of the protective cells has allowed the development of novel compounds that mechanisms that enhance cell survival (3). Hsp90 exerts target specific oncogenic pathways. Molecular therapeutic essential housekeeping functions as a molecular chaperone, such as facilitating protein re-folding, translocation of proteins between cellular compartments, suppression of protein aggregation, supporting functional maturation of Correspondence to: Fumitaka Koga, MD, Ph.D., Department of signaling proteins and facilitating normal protein turnover Urology, Tokyo Medical and Dental University Graduate School, (4). A folding pathway can either lead to a functional, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. Tel/Fax: +81 properly folded client protein, or to degradation of the same 358035295, e-mail: [email protected] protein (5). Under stress, this dual function helps repair or Key Words: Cancer, invasion, metastasis, molecular chaperones, heat- degrade damaged proteins to re-establish protein homeostasis shock protein 90, geldanamycin, molecularly targeted therapeutics, (6). To date, more than 100 proteins have been reported as review. Hsp90 clients (see the website maintained by D Picard, 0250-7005/2009 $2.00+.40 797 ANTICANCER RESEARCH 29: 797-808 (2009) http://www.picard.ch/downloads/Hsp90interactors.pdf). limitless replicative potential, v) self-sufficiency in growth These include many kinases such as ErbB2 (also known as signaling, and vi) ability to evade apoptosis. As shown in HER2/neu), Akt, Bcr-Abl (a fusion protein of BCR and Abl Figure 2, Hsp90 plays a pivotal role in the acquisition and associated with chronic myelogenous leukemia), Raf-1, and maintenance of each of these capabilities. Given the potential cyclin dependent kinase (CDK) 4, as well as transcription of Hsp90 inhibition to simultaneously abrogate the six factors such as hypoxia-inducible factor-1α (HIF-1α), p53, hallmarks of a cancer cell, targeting Hsp90 would appear to and steroid receptors. be a reasonable anticancer strategy. Figure 1 shows nucleotide-dependent cycling of the Hsp90-based super-chaperone machine. Newly synthesized Hsp90 Inhibitors Hsp90 client protein first associates with an Hsp70/Hsp40 chaperone complex (7). This assembly is then linked to The benzoquinoid ansamycin antibiotics, first isolated from Hsp90 via p60Hop, an Hsp90/Hsp70-interacting protein (8). the actinomycete Streptomyces hygroscopicus var. geldanus At this point, Hsp90 is in its ADP-bound conformation. var. nova, include geldanamycin (GA) and its semi-synthetic Replacement of ADP by ATP in an amino-terminal derivatives, 17-allylamino-17-demethoxygeldanamycin nucleotide binding pocket of Hsp90 alters the Hsp90 (17-AAG) and water-soluble 17-demethylaminoethylamino- conformation, releasing the p60Hop and the Hsp70/Hsp40 17-demethoxygeldanamycin (17-DMAG) (16) (Figure 3). complex, and recruiting another set of co-chaperones, GA has shown antitumor activity against v-Src-transformed including p50Cdc37 and p23. This ATP-bound chaperone cancer cells in vivo as well as in vitro (17). GA was initially complex folds and stabilizes client proteins, and temporarily considered to exhibit its antitumor activity by directly holds them in a state that is now ready to bind to ligand or inhibiting tyrosine kinases. However, an in vitro kinase assay respond to a stimulus. If a client protein fails to receive its revealed that GA neither directly interacts with Src nor stimulus or bind to its ligand, it will be recycled through new inhibits its phosphorylating activity. Finally, Hsp90 was chaperone interactions. If the ATP-dependent step does not identified as the direct target of GA (18). take place, the client will eventually undergo ubiquitination Ansamycin Hsp90 inhibitors, radicicol derivatives (19) and proteasomal degradation (9, 10). Thus, ATP/ADP and other small molecule N-terminal inhibitors, as well as nucleotide occupancy of the amino-terminal binding pocket the peptide shepherdin (20, 21) replace the nucleotide in the in Hsp90 drives the Hsp90 super-chaperone machine to bind Hsp90-binding pocket with an affinity greater than ATP or to, chaperone and release client proteins. ADP, thus short-circuiting the Hsp90 chaperone cycle. From the point of view of evolution, Hsp90 functions as a Cycling of the chaperone machine is critical to its function. capacitor of genetic and phenotypic variation (11, 12). The The Hsp90 inhibitors prevent the nucleotide-dependent chaperoning function of Hsp90 can buffer genetic variation cycling and thus interfere with the Hsp90 chaperone function at the protein level, allowing polymorphic variants to as if one stops the rotation of a bicycle wheel by inserting a accumulate silently until they are released in response to stick between the spokes. GA binding promotes stable stress, which creates increased demand for Hsp90 to assembly of the super-chaperone machine that resembles the facilitate refolding of its usual client proteins as well as new, chaperone’s ADP-bound conformation, resulting in targeting stress-destabilized clients. The stock of genetic variation in of the client proteins to the ubiquitin-proteasomal system, certain individuals can thereby exceed the buffering capacity where they are degraded (22) (Figure 4). Thus, Hsp90 of Hsp90 and produce diverse, genotype-specific inhibition uniformly shortens the half-lives of Hsp90 client phonotypes. In this way, previously hidden genetic variations proteins. may become available for natural selection to enhance the Since Hsp90 is essential for the function of normal cells as survival of distinct genotypes within a population. well as tumor cells, one might be concerned that inhibition of its functions might not be selective for malignancy. Both The Cancer Chaperone Hsp90 preclinical and clinical observations, however, have shown that Hsp90 inhibitors can be given in vivo at doses and Cancer is a disease of genetic instability. Although only a schedules that exert antitumor activity without causing host few specific mutations seem to be sufficient for the toxicity (23). This is the case for several Hsp90 inhibitors, development of the malignant phenotype, over 10,000 including a synthetic purine mimetic PU24FCl (24) and the mutations have been found at the time of diagnosis of colon novel peptidomimetic inhibitor of the amino-terminal Hsp90 cancer (13, 14). Such genetic instability allows a cell to nucleotide-binding site, shepherdin (20, 21), as well as eventually acquire six capabilities that characterize 17-AAG and 17-DMAG (25-27).
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