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Mol Biol Cell. 2012 Feb;23(4):602-13. doi: 10.1091/mbc.E11-06-0575. Epub 2011 Dec 21.

A potentially common peptide target in secreted heat shock protein-90α for hypoxia-inducible factor-1α-positive tumors.

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  • 1Department of Dermatology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA.

Abstract

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.

PMID:
22190738
[PubMed - indexed for MEDLINE]
PMCID:
PMC3279389
Free PMC Article

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