Enhancement by HSP90 inhibitor of PGD2-stimulated HSP27 induction in osteoblasts: Suppression of SAPK/JNK and p38 MAP kinase
Woo KimHaruhiko TokudaTetsu KawabataKazuhiko FujitaGo SakaiDaiki NakashimaJunko TachiGen KuroyanagiRie Matsushima‐NishiwakiKumiko TanabeTakanobu OtsukaHiroki IidaOsamu Kozawa
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Heat shock proteins (HSP) are a family of highly conserved proteins, whose expression increases in response to stresses that may threaten cell survival. Over the past decade, heat shock protein 90 (Hsp90) has emerged as a potential therapeutic target for cancer as it plays a vital role in normal cell maturation and acts as a molecular chaperone for proper folding, assembly, and stabilization of many oncogenic proteins. To date, a majority of Hsp90 inhibitors that have been discovered are macrocycles. The relatively rigid conformation provided by the macrocyclic scaffold allows for a selective interaction with a biological target such as Hsp90. This review highlights the discovery and development of nine macrocycles that inhibit the function of Hsp90, detailing their potency and the client proteins affected by Hsp90 inhibition.
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Cytosolic Raf-1 exists in a high molecular weight complex with the heat shock protein Hsp90, the purpose of which is unknown. The benzoquinone ansamycin, geldanamycin, specifically binds to Hsp90 and disrupts certain multimolecular complexes containing this protein. Using this drug, we are able to demonstrate rapid dissociation of both Raf-1-Hsp90 and Raf-1-Ras multimolecular complexes, concomitant with a markedly decreased half-life of the Raf-1 protein. Continued disruption of the Raf-1-Hsp90 complex results in apparent loss of Raf-1 protein from the cell, although Raf-1 synthesis is actually increased. Prevention of Raf-1-Hsp90 complex formation interferes with trafficking of newly synthesized Raf-1 from cytosol to plasma membrane. These data indicate that association with Hsp90 is essential for both Raf-1 protein stability and its proper localization in the cell. Cytosolic Raf-1 exists in a high molecular weight complex with the heat shock protein Hsp90, the purpose of which is unknown. The benzoquinone ansamycin, geldanamycin, specifically binds to Hsp90 and disrupts certain multimolecular complexes containing this protein. Using this drug, we are able to demonstrate rapid dissociation of both Raf-1-Hsp90 and Raf-1-Ras multimolecular complexes, concomitant with a markedly decreased half-life of the Raf-1 protein. Continued disruption of the Raf-1-Hsp90 complex results in apparent loss of Raf-1 protein from the cell, although Raf-1 synthesis is actually increased. Prevention of Raf-1-Hsp90 complex formation interferes with trafficking of newly synthesized Raf-1 from cytosol to plasma membrane. These data indicate that association with Hsp90 is essential for both Raf-1 protein stability and its proper localization in the cell.
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Inhibition of the 90 kDa heat shock protein (Hsp90) family of molecular chaperones represents a promising new chemotherapeutic approach toward the treatment of several cancers. Previous studies have demonstrated that the natural products, radicicol and geldanamycin, are potent inhibitors of the Hsp90 N-terminal ATP binding site. The cocrystal structures of these molecules bound to Hsp90 have been determined, and through molecular modeling and superimposition of these ligands, hybrids of radicicol and geldanamycin have been designed. A series of macrocylic chimeras of radicicol and geldanamycin and the corresponding seco-agents have been prepared and evaluated for both antiproliferative activity and their ability to induce Hsp90-dependent client protein degradation.
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Geldanamycin, an ansamycin-derivative benzoquinone compound, was originally isolated as a natural product with anti-fungal activity. Later, geldanamycin was found to have anti-proliferative activity on tumor cells transformed by oncogene kinases such as v-Src. Geldanamycin neither bind nor inhibit oncogene kinases directly, but specifically binds and inhibits a major molecular chaperone, Hsp90. Hsp90 is a highly abundant and essential cytosolic protein and the expression level of Hsp90 increases by environmental stress. Hsp90 functions as a molecular chaperone by binding to various cellular proteins and supporting the proper folding, stability, and function of target proteins. The Hsp90 client proteins 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 in cooperation with other molecular chaperones such as Cdc37 and FKBP52. Geldanamycin 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 cancer cells and shows anti-cancer activity in experimental animals. Although difficulties with solubility and toxicity should be overcome, 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 clinical trials with encouraging results. Keywords: hsp90, molecular chaperone, geldanamycin, protein kinase, signal transduction, cell growth, cancer chemotherapy
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To examine the biochemical mechanism by which hsp90 exerts its essential positive function on certain signal transduction proteins, we characterized the effects of molybdate and geldanamycin on hsp90 function and structure. Molybdate inhibited hsp90-mediated p56lck biogenesis and luciferase renaturation while enforcing salt-stable interactions with these substrates. Molybdate also reduced the amount of free hsp90 present in cell lysates, inhibited hsp90's ability to bind geldanamycin, and induced resistance to proteolysis at a specific region within the C-terminal domain of hsp90. In contrast, the hsp90 inhibitor geldanamycin prevented hsp90 from assuming natural or molybdate-induced conformations that allow salt-stable interactions with substrates. When these compounds were applied sequentially, the order of addition determined the effects observed, indicating that these agents had opposing effects on hsp90. We conclude that a specific region within the C-terminal domain of hsp90 (near residue 600) determines the mode by which hsp90 interacts with substrates and that the ability of hsp90 to cycle between alternative modes of interaction is obligatory for hsp90 function.
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Geldanamycin and radicicol, antibiotics produced by Streptomycetes and fungi, respectively, were originally discovered many years ago. Only recently was it discovered that they bind with high specificity within the ADP/ATP binding pocket of the Hsp90 molecular chaperone, thereby inhibiting the function of Hsp90. In eukaryotic cells Hsp90 catalyzes the final activation step of many of the most important regulatory proteins. Cells that lose this function are severely compromised and cannot progress through the cell cycle. In cell-culture systems, the administration of geldanamycin induces degradation of several signal transduction proteins of oncological importance. Hsp90 inhibitors are, therefore, now attracting considerable attention as potential antitumor agents; one geldanamycin derivative is already in phase I trials as an anticancer drug. These drugs may also have virucidal, antimalarial and ischemia-protective effects.
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The molecular chaperone HSP90 regulates stability and function of multiple protein kinases. The HSP90-binding drug geldanamycin interferes with this activity and promotes proteasome-dependent degradation of most HSP90 client proteins. Geldanamycin also binds to GRP94, the HSP90 paralog located in the endoplasmic reticulum (ER). Because two of three ER stress sensors are transmembrane kinases, namely IRE1α and PERK, we investigated whether HSP90 is necessary for the stability and function of these proteins. We found that HSP90 associates with the cytoplasmic domains of both kinases. Both geldanamycin and the HSP90-specific inhibitor, 514, led to the dissociation of HSP90 from the kinases and a concomitant turnover of newly synthesized and existing pools of these proteins, demonstrating that the continued association of HSP90 with the kinases was required to maintain their stability. Further, the previously reported ability of geldanamycin to stimulate ER stress-dependent transcription apparently depends on its interaction with GRP94, not HSP90, since geldanamycin but not 514 led to up-regulation of BiP. However, this effect is eventually superseded by HSP90-dependent destabilization of unfolded protein response signaling. These data establish a role for HSP90 in the cellular transcriptional response to ER stress and demonstrate that chaperone systems on both sides of the ER membrane serve to integrate this signal transduction cascade.
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HSP90は主要な細胞内分子シャペロンの一つであり,細胞ストレス状況下で発現量が増大するが,通常でも細胞質にもっとも多く存在するタンパク質の一つである.HSP90は様々な細胞内タンパク質と相互作用してその正確なフォルディングと機能を保証する役割を持つ.HSP90と相互作用するクライアントタンパク質にはプロテインキナーゼやステロイドホルモン受容体等の細胞増殖や分化に重要な役割を果たすシグナル伝達分子が多く含まれる.HSP90はCdc37やFKBP52といった他の分子シャペロンと協調しながら,クライアントタンパク質が正しくシグナルに応答して機能する為に必須の因子としてATP依存的に働いている.ゲルダナマイシンはHSP90のATP-bindingポケットに結合してそのシャペロン機能を抑制する特異的な阻害薬であり,HSP90依存性のクライアントタンパク質の不活性化·不安定化と分解を引き起こす.HSP90のクライアントタンパク質には細胞周期·細胞死や細胞の生存·癌化に関わる機能タンパク質が多く含まれ,ゲルダナマイシン処理でHSP90を阻害すると培養癌細胞の増殖が抑制され,また実験動物での腫瘍縮小効果が観察される.ゲルダナマイシンはHSP90という単一のタンパク質に対する特異的な阻害薬でありながら,細胞周期·細胞分裂·細胞生存シグナル·アポトーシス·ステロイドホルモン作用·ストレス耐性などに関わる多面的なクライアント分子を同時に阻害できるという点で,これまでに無く広範でかつ効果的な抗癌作用を持つ薬剤となり得る.ゲルダナマイシンと同様のHSP90阻害効果を持ちながら腎·肝毒性を軽減した誘導体である17-allylaminogeldanamycin(17-AAG)は既にヒトに対するPhaseIの治験を経て,まもなく癌患者に対するPhaseIIの臨床試験が始められようとしている.
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The Hsp90 molecule, one of the most abundant heat shock proteins in mammalian cells, maintains homeostasis and prevents stress-induced cellular damage. Hsp90 is expressed under normal conditions at a level of about 1-2 Percent of total proteins, while its expression increases 2-10 fold in cancer cells. The two main constitutively expressed isoforms of Hsp90 are known as Hsp90-alpha and Hsp90-beta, and their upregulation is associated with tumor progression, invasion and formation of metastases, as well as development of drug resistance. The Hsp90 is a key target for many newly established, potent anticancer agents containing Hsp90 N-terminal ATP binding inhibitors, such as geldanamycin, and its analogues 17AAG and 17DMAG. The therapeutic usage of geldanamycin has been limited due to its poor water solubility and severe hepatotoxicity. Therefore, its analogues, including 17AAG, 17DMAG, Tanespimycin and Retaspimycin hydrochloride, with improved pharmacokinetic profiles, have been developed.
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