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

Abstract

ETOC: Deregulated/overexpressed HIF-1α is found in many solid tumors, and directly sabotaging it is challenging therapeutically. HIF-1α uses secreted Hsp90α, which uses a key epitope, F-5, for invasion and tumor formation. Drugs that target F-5 may be more effective and less toxic for treatment of HIF-1α–positive tumors.

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.