title: [Molecular chaperone HSP90 as a novel target for cancer chemotherapy].
abstract: HSP90 is one of the major molecular chaperones whose expression level increases by environmental stresses. Even under normal conditions, HSP90 is a highly abundant cytosolic protein and is essential for cell viability. HSP90 is involved in the maintenance of appropriate folding and conformation of many cellular functional proteins. These "HSP90 client proteins" are associated with HSP90 and they include a wide variety of signal-transducing proteins that regulate cell growth and differentiation, such as protein kinases and steroid hormone receptors. HSP90 functions in an ATP-dependent manner with other molecular chaperones such as Cdc37 and FKBP52. An HSP90 inhibitor, geldanamycin, binds the ATP-binding pocket of HSP90 and specifically inhibits the essential ATPase activity of HSP90. Thus, treatment of cells with geldanamycin results in inactivation, destabilization, and degradation of HSP90 client proteins. Because HSP90 client proteins play important roles in the regulation of the cell cycle, cell growth, cell survival, apoptosis, and oncogenesis, geldanamycin obstructs the proliferation of cultured cancer cells and shows anti-cancer activity in experimental animals. Although the precise mechanism of the effect of HSP90 inhibitors on cancer cells remains to be clarified, HSP90 inhibitors will be potential and effective cancer chemotherapeutic drugs with a unique profile. In fact, a modified geldanamycin with lower toxicity, 17-allylaminogeldanamycin (17-AAG), has been examined in phase I clinic trials with encouraging results.
authors.affiliation: Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Kitashirakawa, Oiwake-cho, Sakyo-ku, Kyoto 606-8502, Japan. ymiyata@lif.kyoto-u.ac.jp
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Miyata
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000494:pharmacology; D016227:Benzoquinones; D018797:Cell Cycle Proteins / Q000502:physiology; D018833:Chaperonins; D017321:Clinical Trials, Phase I as Topic; D029721:Drosophila Proteins; D015195:Drug Design; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D047029:Lactams, Macrocyclic; D018832:Molecular Chaperones / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism; D011809:Quinones / Q000378:metabolism / Q000494:pharmacology; D011987:Receptors, Steroid / Q000378:metabolism; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015398:Signal Transduction / Q000502:physiology; D022021:Tacrolimus Binding Proteins
chemical_list: D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; C498362:CDC37 protein, human; D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018832:Molecular Chaperones; D011809:Quinones; D011987:Receptors, Steroid; D017828:Rifabutin; C112765:tanespimycin; D000255:Adenosine Triphosphate; D011494:Protein Kinases; D000251:Adenosine Triphosphatases; D018833:Chaperonins; D022021:Tacrolimus Binding Proteins; C403485:tacrolimus binding protein 4; C001277:geldanamycin