Bortezomib Abolishes Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Resistance via a p21-Dependent Mechanism in Human Bladder and Prostate Cancer Cells

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor family of cytokines that induces apoptosis in some tumor cells but not in normal cells. Unfortunately, many human cancer cell lines are refractory to TRAIL-induced cell death, and the molecular mechanisms underlying resistance are unclear. Here we report that TRAIL resistance was reversed in human bladder and prostate cancer cell lines by the proteasome inhibitor bortezomib (PS-341, Velcade). Synergistic induction of apoptosis occurred within 4 to 6 hours in cells treated with TRAIL plus bortezomib and was associated with accumulation of p21 WAF-1/Cip-1 (p21) and inhibition of cyclin-dependent kinase (cdk) activity. Roscovitine, a specific cdk1/2 inhibitor, also sensitized cells to TRAIL. Silencing p21 expression reduced levels of DNA fragmentation by 50% in cells treated with bortezomib and TRAIL, confirming that p21 was required for the response. Analysis of the TRAIL pathway revealed that caspase-8 processing was enhanced in a p21-dependent fashion in cells exposed to TRAIL and bortezomib as compared with cells treated with TRAIL alone. Thus, all downstream components of the pathway (Bid cleavage, cytochrome c release, and caspase-3 activation) were amplified. These data strongly suggest that p21-mediated cdk inhibition promotes TRAIL sensitivity via caspase-8 activation and that TRAIL and bortezomib should be combined in appropriate in vivo models as a possible approach to solid tumor therapy. (Cancer Res 2005; 65(11): 4902-8)

NF-κB-independent sensitization of glioblastoma cells for TRAIL-induced apoptosis by proteasome inhibition

“…Although some potential mediators of this sensitization effect have been indicated, for example p21 (Lashinger et al, 2005), c-FLIP (Sayers et al, 2003), Bik and Bim (Nikrad et al, 2005), whereas others have been excluded, for instance Bcl-2 (Nencioni et al, 2005), Bax (He et al, 2004) and Bcl-xL (Johnson et al, 2003), the specific contribution of NF-kB to this phenomenon remained unclear. In fact, there is only one other report pointing to a differential role of proteasome versus NF-kB inhibition in the regulation of TRAIL-induced apoptosis in glioblastoma cells, possibly by blocking degradation of active caspases (Kim et al, 2004).…”

Proteasome Inhibitor Bortezomib Increases Radiation Sensitivity in Androgen Independent Human Prostate Cancer Cells

“…Bortezomib, in combination with tumor necrosis factor-␣ (TNF-␣) or TNF-related-apoptosis-inducing ligand shows synergistic effect to induce apoptosis in human prostate and bladder cancer cells. 8,9 Enhanced radiation sensitivity with proteasome inhibition via downregulation of NF-B was first reported by Russo et al 27 in colorectal cancer cells. Pervan et al 28 demonstrated increased radiosensitivity by proteasome inhibition in the TRAMP-C1 prostate cancer tumor model.…”

“…In preclinical studies, it has been reported that bortezomib (previously known as PS-341), which is a strong proteasome inhibitor, induces apoptosis in many solid tumors including prostate cancer cell lines. [8][9][10][11]17,18 Therefore, inhibition of proteasome activity could be a new strategy for the treatment of prostate cancer. In our study, we investigated the effects of bortezomib alone or in combination with radiation on androgen-independent DU145 human prostate cancer cells.…”

“…18,21 In vitro and in vivo studies with bortezomib in androgen-dependent (LNCaP) and androgen-independent (DU145, PC3) prostate cancer cell lines resulted in growth arrest and apoptosis. [8][9][10][11] Studies have shown that bortezomib induces apoptosis of multiple myeloma and prostate cancer cells via inhibition of NF-B. 8,9,22 NF-B is known to be a survival pathway that is overexpressed in androgen-independent prostate cancer cells.…”

“…Bortezomib, a potent inhibitor of the 26S proteasome, has shown significant activity against both androgendependent and androgen-independent prostate cancer in preclinical models. [8][9][10][11][12] A recently completed phase I/II clinical trial of bortezomib in patients with advanced prostate cancer showed its potential for this disease. 13 However, to date, there have been few reports on the combined use of bortezomib with either radiotherapy or chemotherapy to enhance the effects of these established treatment options.…”