title: A potentially common peptide target in secreted heat shock protein-90α for hypoxia-inducible factor-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.
authors.affiliation: Department of Dermatology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA.
authors.forename: Divya
authors.initials: D
authors.lastname: Sahu
authors.forename: Zhengwei
authors.initials: Z
authors.lastname: Zhao
authors.forename: Fred
authors.initials: F
authors.lastname: Tsen
authors.forename: Chieh-Fang
authors.initials: CF
authors.lastname: Cheng
authors.forename: Ryan
authors.initials: R
authors.lastname: Park
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Situ
authors.forename: Jinyao
authors.initials: J
authors.lastname: Dai
authors.forename: Ariana
authors.initials: A
authors.lastname: Eginli
authors.forename: Sharmineh
authors.initials: S
authors.lastname: Shams
authors.forename: Mei
authors.initials: M
authors.lastname: Chen
authors.forename: Tobias S
authors.initials: TS
authors.lastname: Ulmer
authors.forename: Peter
authors.initials: P
authors.lastname: Conti
authors.forename: David T
authors.initials: DT
authors.lastname: Woodley
authors.forename: Wei
authors.initials: W
authors.lastname: Li
mesh_terms: D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D010455:Peptides / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D018841:HSP90 Heat-Shock Proteins; C112969:HSP90AA1 protein, human; D010455:Peptides; D034741:RNA, Small Interfering; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator