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Combination Treatment with Sublethal Ionizing Radiation and the Proteasome Inhibitor, Bortezomib, Enhances Death-Receptor Mediated Apoptosis and Anti-Tumor Immune Attack

Department of Molecular Biology and Genetics, Gaziosmanpasa University, 60250 Tokat, Turkey
Department of Biology, Georgia State University, 161 Jesse Hill Jr. Dr, Atlanta, GA 30303, USA
Department of Clinical Research and Immunology, American Cancer Society, 250 Williams St, Atlanta, GA 30303, USA
Author to whom correspondence should be addressed.
Academic Editor: Terrence Piva
Int. J. Mol. Sci. 2015, 16(12), 30405-30421;
Received: 13 November 2015 / Revised: 8 December 2015 / Accepted: 11 December 2015 / Published: 21 December 2015
(This article belongs to the Collection Radiation Toxicity in Cells)
PDF [2943 KB, uploaded 21 December 2015]


Sub-lethal doses of radiation can modulate gene expression, making tumor cells more susceptible to T-cell-mediated immune attack. Proteasome inhibitors demonstrate broad anti-tumor activity in clinical and pre-clinical cancer models. Here, we use a combination treatment of proteasome inhibition and irradiation to further induce immunomodulation of tumor cells that could enhance tumor-specific immune responses. We investigate the effects of the 26S proteasome inhibitor, bortezomib, alone or in combination with radiotherapy, on the expression of immunogenic genes in normal colon and colorectal cancer cell lines. We examined cells for changes in the expression of several death receptors (DR4, DR5 and Fas) commonly used by T cells for killing of target cells. Our results indicate that the combination treatment resulted in increased cell surface expression of death receptors by increasing their transcript levels. The combination treatment further increases the sensitivity of carcinoma cells to apoptosis through FAS and TRAIL receptors but does not change the sensitivity of normal non-malignant epithelial cells. Furthermore, the combination treatment significantly enhances tumor cell killing by tumor specific CD8+ T cells. This study suggests that combining radiotherapy and proteasome inhibition may simultaneously enhance tumor immunogenicity and the induction of antitumor immunity by enhancing tumor-specific T-cell activity. View Full-Text
Keywords: radiation; proteasome; death receptors; anti-tumor immunity radiation; proteasome; death receptors; anti-tumor immunity

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Cacan, E.; Spring, A.M.; Kumari, A.; Greer, S.F.; Garnett-Benson, C. Combination Treatment with Sublethal Ionizing Radiation and the Proteasome Inhibitor, Bortezomib, Enhances Death-Receptor Mediated Apoptosis and Anti-Tumor Immune Attack. Int. J. Mol. Sci. 2015, 16, 30405-30421.

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