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Selective depletion of heat shock protein 70 (Hsp70) activates a tumor-specific death program that is independent of caspases and bypasses Bcl-2

Item Type:Article
Title:Selective depletion of heat shock protein 70 (Hsp70) activates a tumor-specific death program that is independent of caspases and bypasses Bcl-2
Creators Name:Nylandsted, J. and Rohde, M. and Brand, K. and Bastholm, L. and Elling, F. and Jaattela, M.
Abstract:Heat shock protein 70 is an antiapoptotic chaperone protein highly expressed in human breast tumors and tumor cell lines. Here, we demonstrate that the mere inhibition of its synthesis by adenoviral transfer or classical transfection of antisense Hsp70 cDNA (asHsp70) results in massive death of human breast cancer cells (MDA-MB-468, MCF-7, BT-549, and SK-BR-3), whereas the survival of nontumorigenic breast epithelial cells (HBL-100) or fibroblasts (WI-38) is not affected. Despite the apoptotic morphology as judged by electron microscopy, the asHsp70-induced death was independent of known caspases and the p53 tumor suppressor protein. Furthermore, Bcl-2 and Bcl-XL, which protect tumor cells from most forms of apoptosis, failed to rescue breast cancer cells from asHsp70-induced death. These results show that tumorigenic breast cancer cells depend on the constitutive high expression of Hsp70 to suppress a transformation-associated death program. Neutralization of Hsp70 may open new possibilities for treatment of cancers that have acquired resistance to therapies activating the classical apoptosis pathway.
Keywords:Adenoviridae, Apoptosis, bcl-X Protein, Breast Neoplasms, Carcinoma, Caspases, Complementary DNA, Gene Therapy, Gene Transfer Techniques, HSP70 Heat-Shock Proteins, Neoplastic Cell Transformation, Proto-Oncogene Proteins c-bcl-2
Source:Proceedings of the National Academy of Sciences of the United States of America
ISSN:0027-8424
Publisher:National Academy of Sciences (U.S.A.)
Volume:97
Number:14
Page Range:7871-7876
Date:5 July 2000
Official Publication:http://www.pnas.org/content/97/14/7871.abstract
PubMed:View item in PubMed

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