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A potentially common peptide target in secreted heat shock protein-90α for hypoxia-inducible factor-1α–positive tumors
Deregulated accumulation of hypoxia-inducible factor-1α (HIF-1α) is a hallmark of many solid tumors. Directly targeting HIF-1α for therapeutics is challenging. Our finding that HIF-1α regulates secretion of heat shock protein-90α (Hsp90α) for cell migration raises the exciting possibility that targe...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3279389/ https://www.ncbi.nlm.nih.gov/pubmed/22190738 http://dx.doi.org/10.1091/mbc.E11-06-0575 |
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author | Sahu, Divya Zhao, Zhengwei Tsen, Fred Cheng, Chieh-Fang Park, Ryan Situ, Alan J. Dai, Jinyao Eginli, Ariana Shams, Sharmineh Chen, Mei Ulmer, Tobias S. Conti, Peter Woodley, David T. Li, Wei |
author_facet | Sahu, Divya Zhao, Zhengwei Tsen, Fred Cheng, Chieh-Fang Park, Ryan Situ, Alan J. Dai, Jinyao Eginli, Ariana Shams, Sharmineh Chen, Mei Ulmer, Tobias S. Conti, Peter Woodley, David T. Li, Wei |
author_sort | Sahu, Divya |
collection | PubMed |
description | Deregulated accumulation of hypoxia-inducible factor-1α (HIF-1α) is a hallmark of many solid tumors. Directly targeting HIF-1α for therapeutics is challenging. Our finding that HIF-1α regulates secretion of heat shock protein-90α (Hsp90α) for cell migration raises the exciting possibility that targeting the secreted Hsp90α from HIF-1α–positive tumors has a better clinical outlook. Using the HIF-1α–positive and metastatic breast cancer cells MDA-MB-231, we show that down-regulation of the deregulated HIF-1α blocks Hsp90α secretion and invasion of the cells. Reintroducing an active, but not an inactive, HIF-1α into endogenous HIF-1α–depleted cells rescues both Hsp90α secretion and invasion. Inhibition of Hsp90α secretion, neutralization of secreted Hsp90α action, or removal of the cell surface LRP-1 receptor for secreted Hsp90α reduces the tumor cell invasion in vitro and lung colonization and tumor formation in nude mice. Furthermore, we localized the tumor-promoting effect to a 115–amino acid region in secreted Hsp90α called F-5. Supplementation with F-5 is sufficient to bypass the blockade of HIF-1α depletion and resumes invasion by the tumor cells under serum-free conditions. Because normal cells do not secrete Hsp90α in the absence of stress, drugs that target F-5 should be more effective and less toxic in treatment of HIF-1α–positive tumors in humans. |
format | Online Article Text |
id | pubmed-3279389 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-32793892012-04-30 A potentially common peptide target in secreted heat shock protein-90α for hypoxia-inducible factor-1α–positive tumors Sahu, Divya Zhao, Zhengwei Tsen, Fred Cheng, Chieh-Fang Park, Ryan Situ, Alan J. Dai, Jinyao Eginli, Ariana Shams, Sharmineh Chen, Mei Ulmer, Tobias S. Conti, Peter Woodley, David T. Li, Wei Mol Biol Cell Articles Deregulated accumulation of hypoxia-inducible factor-1α (HIF-1α) is a hallmark of many solid tumors. Directly targeting HIF-1α for therapeutics is challenging. Our finding that HIF-1α regulates secretion of heat shock protein-90α (Hsp90α) for cell migration raises the exciting possibility that targeting the secreted Hsp90α from HIF-1α–positive tumors has a better clinical outlook. Using the HIF-1α–positive and metastatic breast cancer cells MDA-MB-231, we show that down-regulation of the deregulated HIF-1α blocks Hsp90α secretion and invasion of the cells. Reintroducing an active, but not an inactive, HIF-1α into endogenous HIF-1α–depleted cells rescues both Hsp90α secretion and invasion. Inhibition of Hsp90α secretion, neutralization of secreted Hsp90α action, or removal of the cell surface LRP-1 receptor for secreted Hsp90α reduces the tumor cell invasion in vitro and lung colonization and tumor formation in nude mice. Furthermore, we localized the tumor-promoting effect to a 115–amino acid region in secreted Hsp90α called F-5. Supplementation with F-5 is sufficient to bypass the blockade of HIF-1α depletion and resumes invasion by the tumor cells under serum-free conditions. Because normal cells do not secrete Hsp90α in the absence of stress, drugs that target F-5 should be more effective and less toxic in treatment of HIF-1α–positive tumors in humans. The American Society for Cell Biology 2012-02-15 /pmc/articles/PMC3279389/ /pubmed/22190738 http://dx.doi.org/10.1091/mbc.E11-06-0575 Text en © 2012 Sahu et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology. |
spellingShingle | Articles Sahu, Divya Zhao, Zhengwei Tsen, Fred Cheng, Chieh-Fang Park, Ryan Situ, Alan J. Dai, Jinyao Eginli, Ariana Shams, Sharmineh Chen, Mei Ulmer, Tobias S. Conti, Peter Woodley, David T. Li, Wei A potentially common peptide target in secreted heat shock protein-90α for hypoxia-inducible factor-1α–positive tumors |
title | A potentially common peptide target in secreted heat shock protein-90α for hypoxia-inducible factor-1α–positive tumors |
title_full | A potentially common peptide target in secreted heat shock protein-90α for hypoxia-inducible factor-1α–positive tumors |
title_fullStr | A potentially common peptide target in secreted heat shock protein-90α for hypoxia-inducible factor-1α–positive tumors |
title_full_unstemmed | A potentially common peptide target in secreted heat shock protein-90α for hypoxia-inducible factor-1α–positive tumors |
title_short | A potentially common peptide target in secreted heat shock protein-90α for hypoxia-inducible factor-1α–positive tumors |
title_sort | potentially common peptide target in secreted heat shock protein-90α for hypoxia-inducible factor-1α–positive tumors |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3279389/ https://www.ncbi.nlm.nih.gov/pubmed/22190738 http://dx.doi.org/10.1091/mbc.E11-06-0575 |
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