Document Detail


Heat shock protein 70 is secreted from tumor cells by a nonclassical pathway involving lysosomal endosomes.
MedLine Citation:
PMID:  17114456     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Heat shock protein (HSP)70 can be released from tumor cells and stimulate a potent antitumor immune response. However, HSP70 does not contain a consensus secretory signal and thus cannot traverse the plasma membrane by conventional mechanisms. We have observed HSP70 release from intact human prostate carcinoma cell lines (PC-3 and LNCaP) by a mechanism independent of de novo HSP70 synthesis or cell death. This pathway is similar to one used by the leaderless protein IL-1beta. Our studies show that HSP70 release involves transit though an endolysosomal compartment and is inhibited by lysosomotropic compounds. In addition, the rate of HSP70 secretion correlates well with the appearance of the lysosomal marker LAMP1 on the cell surface, further suggesting the role for endolysosomes. The entry of HSP70 into this secretory compartment appears to involve the ABC family transporter proteins and ABC transporter inhibitor glibenclamide antagonizes secretion. Although the cell signals involved in triggering stress induced HSP70 release though this lysosomal pathway are largely unknown, our experiments suggest a regulatory role for extracellular ATP. These mechanisms appear to be shared by IL-1beta secretion. Following release, we observed the binding of extracellular HSP70 to the cell surface of the prostate carcinoma cells. These findings suggest that secreted HSP70 can take part in paracrine or autocrine interactions with adjacent cell surfaces. Our experiments therefore suggest a mechanism for HSP70 secretion and binding to the surface of other cells that may be involved in recognition of the tumor cells by the immune system.
Authors:
Salamatu S Mambula; Stuart K Calderwood
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Journal of immunology (Baltimore, Md. : 1950)     Volume:  177     ISSN:  0022-1767     ISO Abbreviation:  J. Immunol.     Publication Date:  2006 Dec 
Date Detail:
Created Date:  2006-11-20     Completed Date:  2007-01-16     Revised Date:  2007-12-03    
Medline Journal Info:
Nlm Unique ID:  2985117R     Medline TA:  J Immunol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  7849-57     Citation Subset:  AIM; IM    
Affiliation:
Division of Molecular and Cellular Biology, Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, 21-27 Burlington Avenue, Boston, MA 02215, USA.
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MeSH Terms
Descriptor/Qualifier:
ATP-Binding Cassette Transporters / metabolism
Adenosine Triphosphate / metabolism
Blotting, Western
Cell Line, Tumor
Endosomes / metabolism*
Enzyme-Linked Immunosorbent Assay
Extracellular Fluid / chemistry,  metabolism
Fluorescent Antibody Technique
HSP70 Heat-Shock Proteins / secretion*
Humans
Interleukin-1beta / secretion
Lysosomal-Associated Membrane Protein 1 / metabolism
Lysosomes / metabolism*
Male
Prostatic Neoplasms / metabolism*
Protein Transport / physiology*
Grant Support
ID/Acronym/Agency:
CA 047407/CA/NCI NIH HHS; CA 094397/CA/NCI NIH HHS; CA 094397-05S1/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/ATP-Binding Cassette Transporters; 0/HSP70 Heat-Shock Proteins; 0/Interleukin-1beta; 0/Lysosomal-Associated Membrane Protein 1; 56-65-5/Adenosine Triphosphate

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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