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


ABSTRACT: Deregulated accumulation of hypoxia-inducible factor-1? (HIF-1?) is a hallmark of many solid tumors. Directly targeting HIF-1? for therapeutics is challenging. Our finding that HIF-1? regulates secretion of heat shock protein-90? (Hsp90?) for cell migration raises the exciting possibility that targeting the secreted Hsp90? from HIF-1?-positive tumors has a better clinical outlook. Using the HIF-1?-positive and metastatic breast cancer cells MDA-MB-231, we show that down-regulation of the deregulated HIF-1? blocks Hsp90? secretion and invasion of the cells. Reintroducing an active, but not an inactive, HIF-1? into endogenous HIF-1?-depleted cells rescues both Hsp90? secretion and invasion. Inhibition of Hsp90? secretion, neutralization of secreted Hsp90? action, or removal of the cell surface LRP-1 receptor for secreted Hsp90? 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 Hsp90? called F-5. Supplementation with F-5 is sufficient to bypass the blockade of HIF-1? depletion and resumes invasion by the tumor cells under serum-free conditions. Because normal cells do not secrete Hsp90? in the absence of stress, drugs that target F-5 should be more effective and less toxic in treatment of HIF-1?-positive tumors in humans.

SUBMITTER: Sahu D 

PROVIDER: S-EPMC3279389 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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

Sahu Divya D   Zhao Zhengwei Z   Tsen Fred F   Cheng Chieh-Fang CF   Park Ryan R   Situ Alan J AJ   Dai Jinyao J   Eginli Ariana A   Shams Sharmineh S   Chen Mei M   Ulmer Tobias S TS   Conti Peter P   Woodley David T DT   Li Wei W  

Molecular biology of the cell 20111221 4


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 deregul  ...[more]

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