The TRAIL apoptotic pathway mediates proteasome inhibitor induced apoptosis in primary chronic lymphocytic leukemia cells |
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Authors: | Albert F. Kabore Jinmie Sun Xiaojie Hu Kristin McCrea James B. Johnston Spencer B. Gibson |
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Affiliation: | (1) Manitoba Institute of Cell Biology, Cancer Care Manitoba, University of Manitoba, 675 McDermot Ave., Winnipeg, MB, R3E 0V9;(2) Department of Internal Medicine, University of Manitoba, 675 McDermot Ave., Winnipeg, MB, R3E 0V9;(3) Department of Biochemistry and Medical Genetics, University of Manitoba, 675 McDermot Ave., Winnipeg, MB, R3E 0V9 |
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Abstract: | The proteasome inhibitors are a new class of antitumor agents. These inhibitors cause the accumulation of many proteins in the cell with the induction of apoptosis including TRAIL death receptors DR4 and DR5, but the role of the TRAIL apoptotic pathway in proteasome inhibitor cytotoxicity is unknown. Herein, we have demonstrated that the induction of apoptosis by the proteasome inhibitors, MG-132 and PS-341 (bortezomib, Velcade), in primary CLL cells and the Burkitt lymphoma cell line, BJAB, is associated with up-regulation of TRAIL and its death receptors, DR4 and DR5. In addition, FLICE-like inhibitory protein (c-FLIP) protein is decreased. MG-132 treatment increases binding of DR5 to the adaptor protein FADD, and causes caspase-8 activation and cleavage of pro-apoptotic BID. Moreover, DR4:Fc or blockage of DR4 and DR5 expression using RNA interference, which prevents TRAIL apoptotic signaling, blocks proteasome inhibitor induced apoptosis. MG-132 also increases apoptosis and DR5 expression in normal B-cells. However, when the proteasome inhibitors are combined with TRAIL or TRAIL receptor activating antibodies the amount of apoptosis is increased in CLL cells but not in normal B cells. Thus, activation of the TRAIL apoptotic pathway contributes to proteasome inhibitor induced apoptosis in CLL cells. |
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Keywords: | Proteasome inhibitors TRAIL Death receptors Chronic lymphocytic leukemia Apoptosis B cells |
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