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TRAIL and proteasome inhibitors combination induces a robust apoptosis in human malignant pleural mesothelioma cells through Mcl-1 and Akt protein cleavages.
Yuan-B-Z; Chapman-J; Ding-M; Wang-J; Jiang-B; Rojanasakul-Y; Reynolds-SH
BMC Cancer 2013 Mar; 13:140
Background: Malignant pleural mesothelioma (MPM) is an aggressive malignancy closely associated with asbestos exposure and extremely resistant to current treatments. It exhibits a steady increase in incidence, thus necessitating an urgent development of effective new treatments. Methods: Proteasome inhibitors (PIs) and TNFá-Related Apoptosis Inducing Ligand (TRAIL), have emerged as promising new anti-MPM agents. To develop effective new treatments, the proapoptotic effects of PIs, MG132 or Bortezomib, and TRAIL were investigated in MPM cell lines NCI-H2052, NCI-H2452 and NCI-H28, which represent three major histological types of human MPM. Results: Treatment with 0.5-1 uM MG132 alone or 30 ng/mL Bortezomib alone induced a limited apoptosis in MPM cells associated with the elevated Mcl-1 protein level and hyperactive PI3K/Akt signaling. However, whereas 10- 20 ng/ml TRAIL alone induced a limited apoptosis as well, TRAIL and PI combination triggered a robust apoptosis in all three MPM cell lines. The robust proapoptotic activity was found to be the consequence of a positive feedback mechanism-governed amplification of caspase activation and cleavage of both Mcl-1 and Akt proteins, and exhibited a relative selectivity in MPM cells than in non-tumorigenic Met-5A mesothelial cells. Conclusion: The combinatorial treatment using TRAIL and PI may represent an effective new treatment for MPMs.
Asbestos-products; Exposure-levels; Risk-factors; Cancer; Malignancy; Analytical-processes; Cell-biology; Cell-cultures; Cell-damage; Cellular-reactions; Cellular-function; Proteins
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Content source: National Institute for Occupational Safety and Health Education and Information Division