title: Exogenously delivered heat shock protein 70 displaces its endogenous analogue and sensitizes cancer cells to lymphocytes-mediated cytotoxicity.
abstract: Hsp70 chaperone is known to stimulate anti-tumour immunity in a variety of cancer models. Here we demonstrated that the addition of purified recombinant Hsp70 to the culture medium facilitated cancer cell cytolysis by lymphocytes. Importantly, exogenous Hsp70 triggered secretion of the intracellular Hsp70 to a cell surface and extracellular milieu, which played a role in cytolysis because down-regulation of the endogenous Hsp70 reduced both its presence at the cell surface and the lymphocyte-mediated cytolysis. Inhibitors that target both the ATPase and the peptide-binding domains of Hsp70 molecule potently decreased its anti-tumor effect. Using a variety of cell transport markers and inhibitors, we showed that the exchange of exogenous and intracellular Hsp70 is supported by classical and non-classical transport pathways, with a particular role of lipid rafts in the chaperone's intracellular transport. In conclusion, exogenous Hsp70 can eject endogenous Hsp70, thus exerting anticancer activity.
authors.affiliation: Institute of Cytology of Russian Academy of Sciences, St. Petersburg, Russia.
authors.forename: Maxim A
authors.initials: MA
authors.lastname: Shevtsov
authors.forename: Elena Y
authors.initials: EY
authors.lastname: Komarova
authors.forename: Darya A
authors.initials: DA
authors.lastname: Meshalkina
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Bychkova
authors.forename: Nikolai D
authors.initials: ND
authors.lastname: Aksenov
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Abkin
authors.forename: Boris A
authors.initials: BA
authors.lastname: Margulis
authors.forename: Irina V
authors.initials: IV
authors.lastname: Guzhova
mesh_terms: D000818:Animals; D001692:Biological Transport; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D005434:Flow Cytometry; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism*; D018613:Microscopy, Confocal; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism*; D051381:Rats
chemical_list: D018840:HSP70 Heat-Shock Proteins