title: Proteasome inhibitor MG132 upregulates death receptor 5 and cooperates with Apo2L/TRAIL to induce apoptosis in Bax-proficient and -deficient cells.
abstract: Apo2L/TRAIL (tumor necrosis factor-related apoptosis inducing ligand (TRAIL), also known as Apo2L) is a potentially important anticancer agent awaiting clinical trials. Unfortunately, however, some cancer cells exhibit resistance to Apo2L/TRAIL, which could limit the use of this potentially promising anticancer agent. Although the molecular basis of the inherent or acquired resistance to Apo2L/TRAIL remains unclear, previous studies indicate that Bax deficiency can confer resistance to Apo2L/TRAIL. Proteasome inhibition is also emerging as a promising therapeutic strategy to manage human malignancies. Here, we report that proteasome inhibitor MG132 upregulates Apo2L/TRAIL death receptor 5 expression in both Bax-proficient and -deficient HCT116 cells. MG132 effectively cooperated with Apo2L/TRAIL to induce apoptosis in both Bax-proficient and -deficient cells that was coupled with caspases-8 and -3 activation and Bid cleavage. Although both agents in combination also induced cytochrome c and Smac release from mitochondria into cytosol and activated caspase-9 in Bax-proficient cells, their effects on these events were significantly diminished in Bax-deficient cells. These results suggest that Bax is not absolutely required for death receptor 5-dependent apoptotic signals and MG132 by upregulating DR5 effectively cooperates with Apo2L/TRAIL to overcome Bax deficiency-induced resistance to Apo2L/TRAIL. Our results have important clinical implications in that the use of Apo2L/TRAIL and proteasome inhibitors in combination could prove to be a novel therapeutic strategy to manage the Apo2L/TRAIL-resistant tumors.
authors.affiliation: Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, NY 13210, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: He
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.forename: M Saeed
authors.initials: MS
authors.lastname: Sheikh
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004347:Drug Interactions; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000187:drug effects / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects*; D051028:bcl-2-Associated X Protein
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; D007976:Leupeptins; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde