Up-regulation of heat shock protein 27 induces resistance to 17-allylamino-demethoxygeldanamycin through a glutathione-mediated mechanism.

Up-regulation of heat shock protein 27 induces resistance to 17-allylamino-demethoxygeldanamycin through a glutathione-mediated mechanism. Research Abstract Details 

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Up-regulation of heat shock protein 27 induces resistance to 17-allylamino-demethoxygeldanamycin through a glutathione-mediated mechanism. Abstract Text:

Andrea K McCollum,Cynthia J Teneyck,Brian M Sauer,David O Toft,Charles Erlichman,

17-Allylamino-demethoxygeldanamycin (17-AAG), currently in phase I and II clinical trials as an anticancer agent, binds to the ATP pocket of heat shock protein (Hsp90). This binding induces a cellular stress response that up-regulates many proteins including Hsp27, a member of the small heat shock protein family that has cytoprotective roles, including chaperoning of cellular proteins, regulation of apoptotic signaling, and modulation of oxidative stress. Therefore, we hypothesized that Hsp27 expression may affect cancer cell sensitivity to 17-AAG. In colony-forming assays, overexpression of Hsp27 increased cell resistance to 17-AAG whereas down-regulation of Hsp27 by siRNA increased sensitivity. Because Hsp27 is known to modulate levels of glutathione (GSH), we examined cellular levels of GSH and found that it was decreased in cells transfected with Hsp27 siRNA when compared with control siRNA. Treatment with buthionine sulfoximine, an inhibitor of GSH synthesis, also sensitized cells to 17-AAG. Conversely, treatment of Hsp27 siRNA-transfected cells with N-acetylcysteine, an antioxidant and GSH precursor, reversed their sensitivity to 17-AAG. A cell line selected for stable resistance to geldanamycin relative to parent cells showed increased Hsp27 expression. When these geldanamycin- and 17-AAG-resistant cells were transfected with Hsp27 siRNA, 17-AAG resistance was dramatically diminished. Our results suggest that Hsp27 up-regulation has a significant role in 17-AAG resistance, which may be mediated in part through GSH regulation. Clinical modulation of GSH may therefore enhance the efficacy of Hsp90-directed therapy.

Up-regulation of heat shock protein 27 induces resistance to 17-allylamino-demethoxygeldanamycin through a glutathione-mediated mechanism. Publishing Authors By Initials

AK McCollum,CJ Teneyck,BM Sauer,DO Toft,C Erlichman,

For similar genetic processes: gene expression regulation: up-regulation research abstracts see: genetic processes: gene expression regulation: up-regulation research

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Up-regulation of heat shock protein 27 induces resistance to 17-allylamino-demethoxygeldanamycin through a glutathione-mediated mechanism. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Cancer research

VOLUME: 66

Page Numbers: 10967-75

Journal Abbreviation: Cancer Res.

ISSN: 0008-5472

DAY: 15

MONTH: Nov

YEAR: 2006

Up-regulation of heat shock protein 27 induces resistance to 17-allylamino-demethoxygeldanamycin through a glutathione-mediated mechanism. Information

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LANGUAGE: eng

NlmUniqueID: 2984705

Up-regulation of heat shock protein 27 induces resistance to 17-allylamino-demethoxygeldanamycin through a glutathione-mediated mechanism. Keywords Mesh Terms:

KEYWORDS: Up-Regulation

MESH TERMS: genetics

Chemical & Substance for Abstract: Up-regulation of heat shock protein 27 induces resistance to 17-allylamino-demethoxygeldanamycin through a glutathione-mediated mechanism. Information

Substance Name: Glutathione

Registry Number: 70-18-8

Grant and Affiliation Information for Up-regulation of heat shock protein 27 induces resistance to 17-allylamino-demethoxygeldanamycin through a glutathione-mediated mechanism.

AFFILIATION: Department of Molecular Pharmacology, Mayo Clinic College of Medicine, Mayo Clinic and Foundation, Rochester, Minnesota, USA.

Country: United States

AGENCY: United States NCI

GRANT: CA90390

ACRONYM: CA

MEDLINETA: Cancer Res

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