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

• Published in: Oncogene Vol. 22; no. 32; pp. 4953 - 4963
• Main Authors: JOHNSON, Thomas R, STONE, Kimberley, NIKRAD, Malti, YEH, Tammie, ZONG, Wei-Xing, THOMPSON, Craig B, NESTEROV, Alexandre, KRAFT, Andrew S
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 07.08.2003; Nature Publishing Group
• Subjects: Antibodies; Apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins; BAX protein; bcl-2-Associated X Protein; Bcl-x protein; Biological and medical sciences; Bladder cancer; Boronic Acids - pharmacology; Bortezomib; c-FLIP protein; Cancer; Caspase 9; Caspase-8; Caspases - metabolism; Cell death; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Colon cancer; Cytochrome; Cytochrome c; DIABLO protein; DR5 protein; Embryo fibroblasts; FADD protein; Fibroblasts; Fundamental and applied biological sciences. Psychology; Humans; Kinases; Laboratories; Ligands; Membrane Glycoproteins - drug effects; Mitochondria; Molecular and cellular biology; Penicillin; Prostate cancer; Protease Inhibitors - pharmacology; Proteasome inhibitors; Proteins; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-bcl-2 - drug effects; Pyrazines - pharmacology; TNF-Related Apoptosis-Inducing Ligand; TRAIL protein; Tumor Necrosis Factor-alpha - drug effects; Ubiquitination; United States > US; Resistance; Bcl-2; Peptidases; Multicatalytic endopeptidase complex; TRAIL; Enzyme; Caspase; Bax; Hydrolases; Inhibitor; PS-341; Apoptosis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1206656

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.