title: Silencing Hsp25/Hsp27 gene expression augments proteasome activity and increases CD8+ T-cell-mediated tumor killing and memory responses.
abstract: Relatively high expression of Hsp27 in breast and prostate cancer is a predictor of poor clinical outcome. This study elucidates a hitherto unknown mechanism by which Hsp27 regulates proteasome function and modulates tumor-specific T-cell responses. Here, we showed that short-term silencing of Hsp25 or Hsp27 using siRNA or permanent silencing of Hsp25 using lentivirus RNA interference technology enhanced PA28α mRNA expression, PA28α protein expression, and proteasome activity; abrogated metastatic potential; induced the regression of established breast tumors by tumor-specific CD8(+) T cells; and stimulated long-lasting memory responses. The adoptive transfer of reactive CD8(+) T cells from mice bearing Hsp25-silenced tumors efficiently induced the regression of established tumors in nontreated mice which normally succumb to tumor burden. The overexpression of Hsp25 and Hsp27 resulted in the repression of normal proteasome function, induced poor antigen presentation, and resulted in increased tumor burden. Taken together, this study establishes a paradigm shift in our understanding of the role of Hsp27 in the regulation of proteasome function and tumor-specific T-cell responses and paves the way for the development of molecular targets to enhance proteasome function and concomitantly inhibit Hsp27 expression in tumors for therapeutic gain.
authors.affiliation: Division of Investigative Pathology, Scott & White Healthcare and Texas A&M Health Science Center, College of Medicine, Temple, TX 76504, USA. asea@medicine.tamhsc.edu
authors.forename: Ganachari M
authors.initials: GM
authors.lastname: Nagaraja
authors.forename: Punit
authors.initials: P
authors.lastname: Kaur
authors.forename: William
authors.initials: W
authors.lastname: Neumann
authors.forename: Edwina E
authors.initials: EE
authors.lastname: Asea
authors.forename: María A
authors.initials: MA
authors.lastname: Bausero
authors.forename: Gabriele
authors.initials: G
authors.lastname: Multhoff
authors.forename: Alexzander
authors.initials: A
authors.lastname: Asea
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D005786:Gene Expression Regulation; D020868:Gene Silencing; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins; D006801:Humans; D007156:Immunologic Memory; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D018832:Molecular Chaperones; D009368:Neoplasm Transplantation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*
chemical_list: D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D046988:Proteasome Endopeptidase Complex