The proteasome inhibitor PS-341 overcomes TRAIL resistance in Bax and caspase 9-negative or Bcl-xL overexpressing cells.
We demonstrate that PS-341, a small molecule inhibitor of the proteasome, markedly sensitizes resistant prostate, colon, and bladder cancer cells to TNF-like apoptosis-inducing 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.
Johnson
Thomas R
TR
Division of Medical Oncology, University of Colorado Health Sciences Center, 4200 East Ninth Ave., Denver, CO 80262, USA.
Stone
Kimberley
K
Nikrad
Malti
M
Yeh
Tammie
T
Zong
Wei-Xing
WX
Thompson
Craig B
CB
Nesterov
Alexandre
A
Kraft
Andrew S
AS
D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000187:drug effects*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects*; D011719:Pyrazines / Q000494:pharmacology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects*; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; C494811:BCL2L1 protein, human; D001897:Boronic Acids; D008562:Membrane Glycoproteins; D011480:Protease Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D000069286:Bortezomib; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases