title: Curcumin reverses breast tumor exosomes mediated immune suppression of NK cell tumor cytotoxicity.
abstract: An important characteristic of tumors is that they at some point in their development overcome the surveillance of the immune system. Tumors secrete exosomes, multivesicular bodies containing a distinct set of proteins that can fuse with cells of the circulating immune system. Purified exosomes from TS/A breast cancer cells, but not non-exosomal fractions, inhibit (at concentrations of nanograms per ml protein) IL-2-induced natural killer (NK) cell cytotoxicity. The dietary polyphenol, curcumin (diferuloylmethane), partially reverses tumor exosome-mediated inhibition of natural killer cell activation, which is mediated through the impairment of the ubiquitin-proteasome system. Exposure of mouse breast tumor cells to curcumin causes a dose-dependent increase in ubiquitinated exosomal proteins compared to those in untreated TS/A breast tumor cells. Furthermore, exosomes isolated from tumor cells pretreated with curcumin have a much attenuated inhibition of IL-2 stimulated NK cell activation. Jak3-mediated activation of Stat5 is required for tumor cytotoxicity of IL-2 stimulated NK cells. TS/A tumor exosomes strongly inhibit activation of Stat5, whereas the tumor exosomes isolated from curcumin-pretreated tumor cells have a lowered potency for inhibition of IL-2 stimulated NK cell cytotoxicity. These data suggest that partial reversal of tumor exosome-mediated inhibition of NK cell tumor cytotoxicity may account for the anti-cancer properties of curcumin.
authors.affiliation: Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Huang-Ge.Zhang@ccc.uab.edu
authors.forename: Huang-Ge
authors.initials: HG
authors.lastname: Zhang
authors.forename: Helen
authors.initials: H
authors.lastname: Kim
authors.forename: Cunren
authors.initials: C
authors.lastname: Liu
authors.forename: Shaohua
authors.initials: S
authors.lastname: Yu
authors.forename: Jianhua
authors.initials: J
authors.lastname: Wang
authors.forename: William E
authors.initials: WE
authors.lastname: Grizzle
authors.forename: Robert P
authors.initials: RP
authors.lastname: Kimberly
authors.forename: Stephen
authors.initials: S
authors.lastname: Barnes
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D003474:Curcumin / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D007107:Immune System / Q000502:physiology; D007376:Interleukin-2 / Q000276:immunology; D053616:Janus Kinase 3 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D007376:Interleukin-2; D009363:Neoplasm Proteins; D025801:Ubiquitin; D053616:Janus Kinase 3; D003474:Curcumin