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The proteasome inhibitor MG132 potentiates TRAIL receptor agonist-induced apoptosis by stabilizing tBid and Bik in human head and neck squamous cell carcinoma cells

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dc.contributor.authorSung, ES-
dc.contributor.authorPark, KJ-
dc.contributor.authorChoi, HJ-
dc.contributor.authorKim, CH-
dc.contributor.authorKim, YS-
dc.date.accessioned2013-04-29T06:24:48Z-
dc.date.available2013-04-29T06:24:48Z-
dc.date.issued2012-
dc.identifier.issn0014-4827-
dc.identifier.urihttp://repository.ajou.ac.kr/handle/201003/8084-
dc.description.abstractHead and neck squamous cell carcinoma (HNSCC) is often resistant to conventional chemotherapy and thus requires novel treatment regimens. Here, we investigated the effects of the proteasome inhibitor MG132 in combination with tumor necrosis factor-related apoptosis inducing ligand (TRAIL) or agonistic TRAIL receptor 1 (DR4)-specific monoclonal antibody, AY4, on sensitization of TRAIL- and AY4-resistant human HNSCC cell lines. Combination treatment of HNSCC cells synergistically induced apoptotic cell death accompanied by caspase-8, caspase-9, and caspase-3 activation and Bid cleavage into truncated Bid (tBid). Generation and accumulation of tBid through the cooperative action of MG132 with TRAIL or AY4 and Bik accumulation through MG132-mediated proteasome inhibition are critical to the synergistic apoptosis. In HNSCC cells, Bak was constrained by Mcl-1 and Bcl-X(L), but not by Bcl-2. Conversely, Bax did not interact with Mcl-1, Bcl-X(L), or Bcl-2. Importantly, tBid plays a major role in Bax activation, and Bik indirectly activates Bak by displacing it from Mcl-1 and Bcl-X(L), pointing to the synergistic mechanism of the combination treatment. In addition, knockdown of both Mcl-1 and Bcl-X(L) significantly sensitized HNSCC cells to TRAIL and AY4 as a single agent, suggesting that Bak constraint by Mcl-1 and Bcl-X(L) is an important resistance mechanism of TRAIL receptor-mediated apoptotic cell death. Our results provide a novel molecular mechanism for the potent synergy between MG132 proteasome inhibitor and TRAIL receptor agonists in HNSCC cells, suggesting that the combination of these agents may offer a new therapeutic strategy for HNSCC treatment.-
dc.language.isoen-
dc.subject.MESHAntibodies, Monoclonal-
dc.subject.MESHApoptosis-
dc.subject.MESHApoptosis Regulatory Proteins-
dc.subject.MESHBH3 Interacting Domain Death Agonist Protein-
dc.subject.MESHBase Sequence-
dc.subject.MESHCarcinoma, Squamous Cell-
dc.subject.MESHCell Line, Tumor-
dc.subject.MESHDrug Synergism-
dc.subject.MESHGene Knockdown Techniques-
dc.subject.MESHHead and Neck Neoplasms-
dc.subject.MESHHumans-
dc.subject.MESHLeupeptins-
dc.subject.MESHMembrane Proteins-
dc.subject.MESHProteasome Inhibitors-
dc.subject.MESHProtein Stability-
dc.subject.MESHProtein Transport-
dc.subject.MESHProto-Oncogene Proteins c-bcl-2-
dc.subject.MESHRNA Interference-
dc.subject.MESHRNA, Small Interfering-
dc.subject.MESHReceptors, TNF-Related Apoptosis-Inducing Ligand-
dc.subject.MESHTNF-Related Apoptosis-Inducing Ligand-
dc.subject.MESHbcl-2 Homologous Antagonist-Killer Protein-
dc.subject.MESHbcl-2-Associated X Protein-
dc.subject.MESHbcl-X Protein-
dc.titleThe proteasome inhibitor MG132 potentiates TRAIL receptor agonist-induced apoptosis by stabilizing tBid and Bik in human head and neck squamous cell carcinoma cells-
dc.typeArticle-
dc.identifier.pmid22513214-
dc.identifier.urlhttp://linkinghub.elsevier.com/retrieve/pii/S0014-4827(12)00172-3-
dc.contributor.affiliatedAuthor김, 철호-
dc.type.localJournal Papers-
dc.identifier.doi10.1016/j.yexcr.2012.04.003-
dc.citation.titleExperimental cell research-
dc.citation.volume318-
dc.citation.number13-
dc.citation.date2012-
dc.citation.startPage1564-
dc.citation.endPage1576-
dc.identifier.bibliographicCitationExperimental cell research, 318(13). : 1564-1576, 2012-
dc.identifier.eissn1090-2422-
dc.relation.journalidJ000144827-
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Otolaryngology
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