A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors.
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| Title: | A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. |
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| Authors: | Kamal, Adeela, Thao, Lia, Sensintaffar, John, Lin Zhang, Boehm, Marcus F., Fritz, Lawrence C., Burrows, Francis J. |
| Source: | Nature. 9/25/2003, Vol. 425 Issue 6956, p407. 4p. |
| Subjects: | Heat shock proteins, Cancer cells, Binding sites |
| Abstract: | Heat shock protein 90 (Hsp90) is a molecular chaperone that plays a key role in the conformational maturation of oncogenic signalling proteins, including HER-2/ErbB2, Akt, Raf-1, Bcr-Abl and mutated p53. Hsp90 inhibitors bind to Hsp90, and induce the proteasomal degradation of Hsp90 client proteins. Although Hsp90 is highly expressed in most cells, Hsp90 inhibitors selectively kill cancer cells compared to normal cells, and the Hsp90 inhibitor 17-allylaminogeldanamycin (17-AAG) is currently in phase I clinical trials. However, the molecular basis of the tumour selectivity of Hsp90 inhibitors is unknown. Here we report that Hsp90 derived from tumour cells has a 100-fold higher binding affinity for 17-AAG than does Hsp90 from normal cells. Tumour Hsp90 is present entirely in multi-chaperone complexes with high ATPase activity, whereas Hsp90 from normal tissues is in a latent, uncomplexed state. In vitro reconstitution of chaperone complexes with Hsp90 resulted in increased binding affinity to 17-AAG, and increased ATPase activity. These results suggest that tumour cells contain Hsp90 complexes in an activated, high-affinity conformation that facilitates malignant progression, and that may represent a unique target for cancer therapeutics. [ABSTRACT FROM AUTHOR] |
| Copyright of Nature is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
| Database: | Psychology and Behavioral Sciences Collection |
| FullText | Links: – Type: pdflink Text: Availability: 0 |
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| Header | DbId: pbh DbLabel: Psychology and Behavioral Sciences Collection An: 10912354 AccessLevel: 6 PubType: Academic Journal PubTypeId: academicJournal PreciseRelevancyScore: 0 |
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| Items | – Name: Title Label: Title Group: Ti Data: A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Kamal%2C+Adeela%22">Kamal, Adeela</searchLink><br /><searchLink fieldCode="AR" term="%22Thao%2C+Lia%22">Thao, Lia</searchLink><br /><searchLink fieldCode="AR" term="%22Sensintaffar%2C+John%22">Sensintaffar, John</searchLink><br /><searchLink fieldCode="AR" term="%22Lin+Zhang%22">Lin Zhang</searchLink><br /><searchLink fieldCode="AR" term="%22Boehm%2C+Marcus+F%2E%22">Boehm, Marcus F.</searchLink><br /><searchLink fieldCode="AR" term="%22Fritz%2C+Lawrence+C%2E%22">Fritz, Lawrence C.</searchLink><br /><searchLink fieldCode="AR" term="%22Burrows%2C+Francis+J%2E%22">Burrows, Francis J.</searchLink> – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%22Nature%22">Nature</searchLink>. 9/25/2003, Vol. 425 Issue 6956, p407. 4p. – Name: Subject Label: Subjects Group: Su Data: <searchLink fieldCode="DE" term="%22Heat+shock+proteins%22">Heat shock proteins</searchLink><br /><searchLink fieldCode="DE" term="%22Cancer+cells%22">Cancer cells</searchLink><br /><searchLink fieldCode="DE" term="%22Binding+sites%22">Binding sites</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: Heat shock protein 90 (Hsp90) is a molecular chaperone that plays a key role in the conformational maturation of oncogenic signalling proteins, including HER-2/ErbB2, Akt, Raf-1, Bcr-Abl and mutated p53. Hsp90 inhibitors bind to Hsp90, and induce the proteasomal degradation of Hsp90 client proteins. Although Hsp90 is highly expressed in most cells, Hsp90 inhibitors selectively kill cancer cells compared to normal cells, and the Hsp90 inhibitor 17-allylaminogeldanamycin (17-AAG) is currently in phase I clinical trials. However, the molecular basis of the tumour selectivity of Hsp90 inhibitors is unknown. Here we report that Hsp90 derived from tumour cells has a 100-fold higher binding affinity for 17-AAG than does Hsp90 from normal cells. Tumour Hsp90 is present entirely in multi-chaperone complexes with high ATPase activity, whereas Hsp90 from normal tissues is in a latent, uncomplexed state. In vitro reconstitution of chaperone complexes with Hsp90 resulted in increased binding affinity to 17-AAG, and increased ATPase activity. These results suggest that tumour cells contain Hsp90 complexes in an activated, high-affinity conformation that facilitates malignant progression, and that may represent a unique target for cancer therapeutics. [ABSTRACT FROM AUTHOR] – Name: AbstractSuppliedCopyright Label: Group: Ab Data: <i>Copyright of Nature is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.) |
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| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1038/nature01913 Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 4 StartPage: 407 Subjects: – SubjectFull: Heat shock proteins Type: general – SubjectFull: Cancer cells Type: general – SubjectFull: Binding sites Type: general Titles: – TitleFull: A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Kamal, Adeela – PersonEntity: Name: NameFull: Thao, Lia – PersonEntity: Name: NameFull: Sensintaffar, John – PersonEntity: Name: NameFull: Lin Zhang – PersonEntity: Name: NameFull: Boehm, Marcus F. – PersonEntity: Name: NameFull: Fritz, Lawrence C. – PersonEntity: Name: NameFull: Burrows, Francis J. IsPartOfRelationships: – BibEntity: Dates: – D: 25 M: 09 Text: 9/25/2003 Type: published Y: 2003 Identifiers: – Type: issn-print Value: 00280836 Numbering: – Type: volume Value: 425 – Type: issue Value: 6956 Titles: – TitleFull: Nature Type: main |
| ResultId | 1 |
