{"@context":{"@vocab":"https://cir.nii.ac.jp/schema/1.0/","rdfs":"http://www.w3.org/2000/01/rdf-schema#","dc":"http://purl.org/dc/elements/1.1/","dcterms":"http://purl.org/dc/terms/","foaf":"http://xmlns.com/foaf/0.1/","prism":"http://prismstandard.org/namespaces/basic/2.0/","cinii":"http://ci.nii.ac.jp/ns/1.0/","datacite":"https://schema.datacite.org/meta/kernel-4/","ndl":"http://ndl.go.jp/dcndl/terms/","jpcoar":"https://github.com/JPCOAR/schema/blob/master/2.0/"},"@id":"https://cir.nii.ac.jp/crid/1361699994602738176.json","@type":"Article","productIdentifier":[{"identifier":{"@type":"DOI","@value":"10.1073/pnas.0805354105"}},{"identifier":{"@type":"URI","@value":"https://pnas.org/doi/pdf/10.1073/pnas.0805354105"}}],"dc:title":[{"@value":"Inhibition of Hsp90 activates osteoclast c-Src signaling and promotes growth of prostate carcinoma cells in bone"}],"description":[{"type":"abstract","notation":[{"@value":"<jats:p>\n            Hsp90 inhibitors are being evaluated extensively in patients with advanced cancers. However, the impact of Hsp90 inhibition on signaling pathways in normal tissues and the effect that this may have on the antitumor activity of these molecularly targeted drugs have not been rigorously examined. Breast and prostate carcinomas are among those cancers that respond to Hsp90 inhibitors in animal xenograft models and in early studies in patients. Because these cancers frequently metastasize to bone, it is important to determine the impact of Hsp90 inhibitors in the bone environment. In the current study, we show that, in contrast to its activity against prostate cancer cells\n            <jats:italic>in vitro</jats:italic>\n            and its inhibition of s.c. prostate cancer xenografts, the Hsp90 inhibitor 17-AAG stimulates the intraosseous growth of PC-3M prostate carcinoma cells. This activity is mediated not by a direct effect on the tumor but by Hsp90-dependent stimulation of osteoclast maturation. Hsp90 inhibition transiently activates osteoclast Src kinase and promotes Src-dependent Akt activation. Both kinases are key drivers of osteoclast maturation, and three agents that block osteoclastogenesis, the Src inhibitor dasatinib, the bisphosphonate alendronate, and the osteoclast-specific apoptosis-inducer reveromycin A, markedly reduced 17-AAG-stimulated tumor growth in bone. These data emphasize the importance of understanding the complex role played by Hsp90 in regulating signal transduction pathways in normal tissues as well as in cancer cells, and they demonstrate that drug-dependent modulation of the local tumor environment may profoundly affect the antitumor efficacy of Hsp90-directed therapy.\n          </jats:p>"}]}],"creator":[{"@id":"https://cir.nii.ac.jp/crid/1381699994602738176","@type":"Researcher","foaf:name":[{"@value":"Akihiro Yano"}],"jpcoar:affiliationName":[{"@value":"*Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Building 10, Room 1-5940, Bethesda, MD 20892;"}]},{"@id":"https://cir.nii.ac.jp/crid/1381699994602738180","@type":"Researcher","foaf:name":[{"@value":"Shinji Tsutsumi"}],"jpcoar:affiliationName":[{"@value":"*Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Building 10, Room 1-5940, Bethesda, MD 20892;"}]},{"@id":"https://cir.nii.ac.jp/crid/1381699994602738182","@type":"Researcher","foaf:name":[{"@value":"Shiro Soga"}],"jpcoar:affiliationName":[{"@value":"*Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Building 10, Room 1-5940, Bethesda, MD 20892;"}]},{"@id":"https://cir.nii.ac.jp/crid/1381699994602738179","@type":"Researcher","foaf:name":[{"@value":"Min-Jung Lee"}],"jpcoar:affiliationName":[{"@value":"Medical Oncology Branch, National Cancer Institute, Bethesda, MD 20892; and"}]},{"@id":"https://cir.nii.ac.jp/crid/1381699994602738181","@type":"Researcher","foaf:name":[{"@value":"Jane Trepel"}],"jpcoar:affiliationName":[{"@value":"Medical Oncology Branch, National Cancer Institute, Bethesda, MD 20892; and"}]},{"@id":"https://cir.nii.ac.jp/crid/1381699994602738177","@type":"Researcher","foaf:name":[{"@value":"Hiroyuki Osada"}],"jpcoar:affiliationName":[{"@value":"Antibiotics Laboratory, Discovery Research Institute, RIKEN, Saitama, 351-0198 Japan"}]},{"@id":"https://cir.nii.ac.jp/crid/1381699994602738178","@type":"Researcher","foaf:name":[{"@value":"Len Neckers"}],"jpcoar:affiliationName":[{"@value":"*Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Building 10, Room 1-5940, Bethesda, MD 20892;"}]}],"publication":{"publicationIdentifier":[{"@type":"PISSN","@value":"00278424"},{"@type":"EISSN","@value":"10916490"}],"prism:publicationName":[{"@value":"Proceedings of the National Academy of Sciences"}],"dc:publisher":[{"@value":"Proceedings of the National Academy of Sciences"}],"prism:publicationDate":"2008-10-07","prism:volume":"105","prism:number":"40","prism:startingPage":"15541","prism:endingPage":"15546"},"reviewed":"false","url":[{"@id":"https://pnas.org/doi/pdf/10.1073/pnas.0805354105"}],"createdAt":"2008-10-07","modifiedAt":"2022-04-12","relatedProduct":[{"@id":"https://cir.nii.ac.jp/crid/1360004233981910144","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"5-Azacytidine-induced Protein 2 (AZI2) Regulates Bone Mass by Fine-tuning Osteoclast Survival"}]},{"@id":"https://cir.nii.ac.jp/crid/1360013168765459712","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"A novel role of HSP90 in regulating osteoclastogenesis by abrogating Rab11b-driven transport"}]},{"@id":"https://cir.nii.ac.jp/crid/1360283692122452608","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Identification of Middle Chain Fatty Acyl-CoA Ligase Responsible for the Biosynthesis of 2-Alkylmalonyl-CoAs for Polyketide Extender Unit"}]},{"@id":"https://cir.nii.ac.jp/crid/1360283696329101440","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Methylglyoxal, a glycolysis side-product, induces Hsp90 glycation and YAP-mediated tumor growth and metastasis"}]},{"@id":"https://cir.nii.ac.jp/crid/1360285708401082240","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Reveromycin A biosynthesis uses RevG and RevJ for stereospecific spiroacetal formation"}]},{"@id":"https://cir.nii.ac.jp/crid/1360567183362071296","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Creation of novel reveromycin derivatives by alcohol-added fermentation"}]},{"@id":"https://cir.nii.ac.jp/crid/1360848654729675904","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Identification of a novel compound that inhibits osteoclastogenesis by suppressing nucleoside transporters"}]},{"@id":"https://cir.nii.ac.jp/crid/1360848658339106176","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Chemical and biological studies of reveromycin A"}]},{"@id":"https://cir.nii.ac.jp/crid/1360848658911741184","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Structure-Function Analyses of Cytochrome P450revI Involved in Reveromycin A Biosynthesis and Evaluation of the Biological Activity of Its Substrate, Reveromycin T"}]},{"@id":"https://cir.nii.ac.jp/crid/1360861704795007488","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Studies on Streptomyces sp. 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