The Proteasome Inhibitor PS-341 (Bortezomib) Up-Regulates DR5 Expression Leading to Induction of Apoptosis and Enhancement of TRAIL-Induced Apoptosis Despite Up-Regulation of c-FLIP and Survivin Expression in Human NSCLC Cells

Abstract

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 shown 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 show that PS-341 induced caspase-8-dependent apoptosis, cooperated with TRAIL to induce apoptosis, and up-regulated death receptor 5 (DR5) expression in human non-small cell lung cancer (NSCLC) cells. DR5 induction correlated with the ability of PS-341 to induce apoptosis. Blockage of PS-341-induced DR5 up-regulation using DR5 small interfering RNA (siRNA) rendered cells less sensitive to apoptosis induced by either PS-341 or its combination with TRAIL, indicating that DR5 upregulation mediates PS-341-induced apoptosis and enhancement of TRAIL-induced apoptosis in human NSCLC cells. We exclude the involvement of c-FLIP and survivin in mediating these events because c-FLIP (i.e., FLIP S ) and survivin protein levels were actually elevated on 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 up-regulation in PS-341-induced apoptosis and enhancement of TRAIL-induced apoptosis in human NSCLC cells. [Cancer Res 2007;67(10):4981-8]

Nuclear Factor-κB Inhibition by Parthenolide Potentiates the Efficacy of Taxol in Non–Small Cell Lung Cancer In vitro and In vivo

“…However, the advantage of soluble inhibitors is that their delivery would be easier and more efficient than gene transfer. Small molecules that inhibit IKK activity have indeed been described, and some of these molecules have been shown to induce apoptosis in cancer cells (19)(20)(21)(31)(32)(33). However, compounds that inhibit IKK with very high affinities have not been reported.…”

Inostamycin enhanced TRAIL-induced apoptosis through DR5 upregulation on the cell surface

“…Because of the limitations of TRAIL-induced cytotoxicity, the combination of TRAIL with other small molecule compounds has been postulated as strategy to potentiate the cytotoxicity of TRAIL and its therapeutic applications. Indeed, it was reported that several chemotherapeutic agents and natural products, such as CDDP, 10 etoposide, 10,11 doxorubicin, 12 PS-341 (bortezomib), 13 tunicamycin, 14 rottlerin, 15 brandisianins, 16 silibinin 17 and sodium butyrate, 18 were succeeded to cause the sensitization of TRAIL-resistant tumor cells to TRAIL-induced apoptosis.…”

Bortezomib induces apoptosis via Bim and Bik up-regulation and synergizes with cisplatin in the killing of head and neck squamous cell carcinoma cells

“…Up-regulation of proapoptotic Noxa is frequently observed in bortezomib-treated cells and has been shown to mediate apoptosis induction by this agent in cell lines representing multiple myeloma (16,17), non-small cell lung cancer (18), mantle cell lymphoma (19,20), and melanoma (17). Moreover, the ability of bortezomib to sensitize non-small cell lung cancer, myeloid leukemia, and renal carcinoma cells to tumor necrosis factor -related apoptosis-inducing ligand is associated with up-regulation of the DR5 death receptor and down-regulation of c-FLIP (21,22), whereas tumor necrosis factor -related apoptosis-inducing ligand sensitization of prostate and colon cancer cells has been reported to involve Bik and Bim (23 -25).…”