The proteasome inhibitor PS-341 overcomes TRAIL resistance in Bax and caspase 9-negative or Bcl-xL overexpressing cells

Abstract

We demonstrate that PS-341, a small molecule inhibitor of the proteasome, markedly sensitizes resistant prostate, colon, and bladder cancer cells to TNF-like apoptosisinducing ligand (TRAIL)-induced apoptosis irrespective of Bcl-xL overexpression. PS-341 treatment by itself does not affect the levels of Bax, Bak, caspases 3 and 8, c-Flip or FADD, but elevates levels of TRAIL receptors DR4 and DR5. This increase in receptor protein levels is associated with the ubiquitination of the DR5 protein.When PS-341 is combined with TRAIL, the levels of activated caspase 8 and cleaved Bid are substantially increased. In Bax-negative TRAIL-resistant HC-4 colon cancer cells, the combination of PS-341 and TRAIL overcomes the block to activation of the mitochondrial pathway and causes SMAC and cytochrome c release followed by apoptosis. Similarly, murine embryonic fibroblasts lacking Bax undergo apoptosis when exposed to the combination of PS-341 and TRAIL; however, fibroblasts lacking Bak are significantly resistant. Taken together, these findings indicate that PS-341 enhances TRAIL-induced apoptosis by increasing the cleavage of caspase 8, causing Bak-dependent release of mitochondrial proapoptotic proteins.

Proteasome inhibitor‐induced apoptosis in human monocyte‐derived dendritic cells

“…Bax up-regulation via bortezomib was accompanied by migration of this molecule from the cytosol to the membrane fraction in DC, which is strongly suggestive of Bax insertion into the mitochondria to favor release of pro-apoptotic substrates. Evidence in Bax-deficient tumor cells indicates that Bax is a key mediator of proteasome inhibitor-induced apoptosis (I.R., G.D.B., unpublished observations, and [40,42]). Therefore, our data delineate a suitable mechanism for the initiation of the apoptotic cascade in DC by bortezomib and related drugs.…”

Analysis of changes in the proteome of HL-60 promyeloid leukemia cells induced by the proteasome inhibitor PSI

“…While a significant contribution of the intrinsic apoptosis pathway to proteasome inhibitor mediated cell death is undisputed, the impact of the extrinsic apoptosis pathway involving death receptor activation by their corresponding ligands and caspase-8 activation is currently less clear. However, increased levels of TRADD, FADD, Fas and FasL in PSI-treated HL60 cells supported a role of the extrinsic pathway of apoptosis, and sensitization of various tumor cell lines to TRAIL induced apoptosis by the proteasome inhibitor bortezomib has been reported, which is due to upregulation of TRAIL itself as well as of its receptor Decoy receptor 5 (DR5) [51,52]. Thus, administration of proteasome inhibitors results in the stimulation of a proapoptotic autocrine loop by signaling via death receptor family members.…”

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

“…Proteasome inhibitors have previously been reported to enhance TRAIL-induced apoptosis in a variety of cancers, for example glioblastoma (Kasuga et al, 2004;Kim et al, 2004;Yin et al, 2005) and prostate, colon or bladder cancer (Johnson et al, 2003), as well as primary kerationocytes (Leverkus et al, 2003). 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.…”

“…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).…”