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• W1420095918 abstract "2406 The proteasome inhibitor PS-341 (Bortezomib or Velcade), an approved drug for treatment of patients with multiple myeloma, is currently being tested in clinical trials against various malignancies including lung cancer. Preclinical studies have demonstrated that PS-341 induces apoptosis and enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human cancer cells with undefined mechanisms. In the present study, we focused on revealing the mechanisms by which PS-341 induces apoptosis and enhances TRAIL-induced apoptosis in human lung cancer cells. PS-341 increased cleavage of caspase-8 and apoptosis. Prevention of caspase-8 activation by silencing caspase-8 expression using caspase-8 small interfering RNA (siRNA) abrogated PS-341-induced apoptosis. These results indicate that PS-341 induces caspase-8-depenent apoptosis. PS-341 induced expression of death receptor 5 (DR5) and cooperated with TRAIL to induce apoptosis in human lung cancer cells. Importantly, DR5 induction by PS-341 correlated with PS-341’s ability to induce apoptosis, whereas blockage of PS-341-induced DR5 upregulation using DR5 siRNA rendered cells less sensitive to apoptosis induced by either PS-341 or its combination with TRAIL. These results demonstrate that DR5 upregulation mediates PS-341-induced apoptosis and enhancement of TRAIL-induced apoptosis in human lung cancer cells. We exclude the involvement of c-FLIP and survivin in mediating these events because c-FLIP (i.e., FLIPS) and survivin protein levels were actually elevated upon exposure to PS-341. Reduction of c-FLIP with c-FLIP siRNA sensitized cells to PS-341-induced apoptosis, suggesting that c-FLIP elevation protects cells from PS-341-induced apoptosis. Thus, the present study highlights the important role of DR5 upregulation in PS-341-induced apoptosis and enhancement of TRAIL-induced apoptosis. (Supported by GCC Distinguished Cancer Scholar award and DOD grant W81XWH-04-1-0142-VITAL)" @default.
• W1420095918 created "2016-06-24" @default.
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• W1420095918 date "2007-05-01" @default.
• W1420095918 modified "2023-09-23" @default.
• W1420095918 title "The proteasome inhibitor PS-341 (Bortezomib) upregulates death receptor 5 expression leading to induction of apoptosis and enhancement of TRAIL-induced apoptosis despite increase of c-FLIP and survivin in human lung cancer cells." @default.
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