Bortezomib Sensitizes Human Esophageal Squamous Cell Carcinoma Cells to TRAIL–Mediated Apoptosis via Activation of Both Extrinsic and Intrinsic Apoptosis Pathways
| Autor: | Uhi Toh, Masayoshi Kage, Teruhiko Fujii, Naoko Seki, Kazuo Shirouzu, Yoshito Akagi, Motoshi Miyagi, Jingo Kusukawa, Thomas J. Sayers, Hideaki Yamana |
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| Rok vydání: | 2010 |
| Předmět: |
Death Domain Receptor Signaling Adaptor Proteins
Cancer Research Esophageal Neoplasms Cell CASP8 and FADD-Like Apoptosis Regulating Protein Apoptosis Article Bortezomib TNF-Related Apoptosis-Inducing Ligand Cell Line Tumor hemic and lymphatic diseases medicine Humans neoplasms Caspase Death domain biology Intrinsic apoptosis Drug Synergism Boronic Acids digestive system diseases Up-Regulation Cell biology Receptors TNF-Related Apoptosis-Inducing Ligand medicine.anatomical_structure Oncology Drug Resistance Neoplasm Caspases Pyrazines Carcinoma Squamous Cell biology.protein Cancer research Proteasome inhibitor Drug Screening Assays Antitumor Signal transduction Signal Transduction medicine.drug |
| Zdroj: | Molecular Cancer Therapeutics. 9:1842-1851 |
| ISSN: | 1538-8514 1535-7163 |
| Popis: | Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive human cancers, and novel treatment modalities are required. We investigated the therapeutic potential of the tumor necrosis factor–related apoptosis-inducing ligand (TRAIL/Apo2L) in combination with the proteasome inhibitor bortezomib (Velcade) on human ESCC cell lines. Bortezomib enhanced the susceptibility to TRAIL in 12 of the 15 ESCC cell lines tested, although most showed low sensitivity to TRAIL as a single agent. The enhancement of TRAIL-induced apoptosis by bortezomib was caspase dependent. Increased processing of caspase-8 often accompanied enhancement of TRAIL-induced apoptosis by bortezomib. However, the increased cell surface expression of death receptors observed on bortezomib treatment did not seem to be crucial for this effect. For some ESCC, bortezomib treatment resulted in a more efficient recruitment of caspase-8 and the Fas-associated death domain to the death-inducing signaling complex. Additional downregulation of the cellular FLICE-inhibitory protein long isoform [c-FLIP(L)] could cooperate in the activation of the extrinsic pathway in some cases. For other ESCC, the crucial effect of bortezomib treatment seemed to be increased signaling via the intrinsic apoptotic pathway on subsequent exposure to TRAIL. Thus, bortezomib could sensitize ESCC to TRAIL apoptosis by multiple molecular mechanisms of action. Therefore, the combination of bortezomib and TRAIL might be a novel therapeutic strategy for ESCC patients who fail to respond to standard chemoradiotherapy that predominantly targets the mitochondrial apoptotic pathway. Mol Cancer Ther; 9(6); 1842–51. ©2010 AACR. |
| Databáze: | OpenAIRE |
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