Malignant mesothelioma cells are rapidly sensitized to TRAIL-induced apoptosis by low-dose anisomycin via Bim
| Autor: | Ki-Up Kim, Abigail E. Hunt, Keith S. Abayasiriwardana, Kevin K. Lee, Dario Barbone, V. Courtney Broaddus, Gerard I. Evan, Tobias B. Dansen, Claire Vivo |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Mesothelioma
Cancer Research Small interfering RNA Immunoblotting Apoptosis Biology Cycloheximide Ligands TNF-Related Apoptosis-Inducing Ligand chemistry.chemical_compound Proto-Oncogene Proteins Tumor Cells Cultured medicine Humans Electrophoresis Gel Two-Dimensional Annexin A5 Phosphorylation RNA Small Interfering Anisomycin Sensitization Etoposide Protein Synthesis Inhibitors Gene knockdown Bcl-2-Like Protein 11 Kinase JNK Mitogen-Activated Protein Kinases Membrane Proteins Drug Synergism Antineoplastic Agents Phytogenic Combined Modality Therapy medicine.anatomical_structure Oncology chemistry Immunology Cancer research Tumor necrosis factor alpha Apoptosis Regulatory Proteins |
| Zdroj: | Molecular Cancer Therapeutics. 6:2766-2776 |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.mct-07-0278 |
| Popis: | Tumor necrosis factor–related apoptosis inducing ligand (TRAIL) holds promise for the treatment of tumors; however, many tumors are resistant to TRAIL alone. We previously showed that resistant malignant mesothelioma cells are sensitized to TRAIL-induced apoptosis by diverse toxic insults including chemotherapy, irradiation, or protein translation inhibitors such as cycloheximide. In seeking nontoxic sensitizers for TRAIL, we tested the protein translation inhibitor anisomycin at subtoxic concentrations 10- to 100-fold below those reported to inhibit protein translation. At these low concentrations (25 ng/mL), anisomycin potently and rapidly sensitized mesothelioma cells to TRAIL-induced apoptosis. Moreover, such sensitization occurred in malignant but not in nonmalignant mesothelial cells. Sensitization by anisomycin was dependent on Bid, indicating a role for mitochondrial amplification in the apoptotic synergy with TRAIL signaling. Consistent with this, we found that anisomycin induces rapid accumulation of the BH3-only protein Bim; moreover, small interfering RNA knockdown of Bim inhibits anisomycin-induced sensitization. Bim accumulation seems not to be transcriptional; instead, it is associated with Bim phosphorylation and increased stability, both consistent with the activation of c-jun NH2-terminal kinase signals by anisomycin. Overall, our data indicate that the rapid and selective sensitization by anisomycin in mesothelioma cells is mediated by posttranslational potentiation of Bim, which primes the cells for apoptosis via the death receptor pathway. Such subtoxic approaches to sensitization may enhance the value of TRAIL in cancer therapy. [Mol Cancer Ther 2007;6(10):2766–76] |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|