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Research Articles: Therapeutics, Targets, and Development

Malignant mesothelioma cells are rapidly sensitized to TRAIL-induced apoptosis by low-dose anisomycin via Bim

¹ Lung Biology Center, San Francisco General Hospital and ² Cancer Research Institute, UCSF Comprehensive Cancer Center, University of California San Francisco, San Francisco, California

Requests for reprints: V. Courtney Broaddus, Lung Biology Center, Box 0854, University of California San Francisco, San Francisco, CA 94110-0854. Phone: 415-206-3513; Fax: 415-206-4123. E-mail: cbroaddus{at}medsfgh.ucsf.edu

Abstract

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]

Grant support: NIH grant RO1 CA95671 and the Buzzi-Unicem Foundation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

³ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 4/16/07; revised 7/ 6/07; accepted 8/31/07.

This article has been cited by other articles:

				D. Barbone, T.-M. Yang, J. R. Morgan, G. Gaudino, and V. C. Broaddus Mammalian Target of Rapamycin Contributes to the Acquired Apoptotic Resistance of Human Mesothelioma Multicellular Spheroids J. Biol. Chem., May 9, 2008; 283(19): 13021 - 13030. [Abstract] [Full Text] [PDF]