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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...

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Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2012
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.
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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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