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Nagaraja, G.M.* ; Kaur, P.* ; Neumann, W.* ; Asea, E.E.* ; Bausero, M.A.* ; Multhoff, G. ; Asea, A.*

Silencing hsp25/hsp27 gene expression augments proteasome activity and increases CD8+ T-cell-mediated tumor killing and memory responses.

Cancer Prev. Res. 5, 122-137 (2012)
DOI
Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Natural-killer-cells ; Shock-protein 27 ; Mhc Class-i ; Heat-shock-protein-70 Hsp70 ; Membrane Expression ; Androgen Ablation ; Drug-resistance ; Leukemic Blasts ; Prostate-cancer ; Activator Pa28
ISSN (print) / ISBN 1940-6207
e-ISSN 1940-6215
Quellenangaben Volume: 5, Issue: 1, Pages: 122-137 Article Number: , Supplement: ,
Publisher American Association for Cancer Research (AACR)
Reviewing status Peer reviewed