Abstract #404: TRAIL enhances proteasome inhibitor-induced apoptosis in human malignant pleural mesothelioma cells through promoting caspase activation and Mcl-1 protein cleavage

Malignant pleural mesothelioma (MPM), caused mainly by occupational or environmental exposure to asbestos, is an aggressive malignancy with a very poor prognosis. General resistance to current treatments and steady increase in the incidence necessitate an urgent need for developing new treatments for MPM. Proteasome inhibitors (PIs) have emerged as new promising agents for treating MPM. PIs has been found to be able to induce a moderate apoptosis in human MPM cells through activating the intrinsic apoptosis pathway, which is regulated by the concomitantly elevated Mcl-1 protein. TRAIL is a tumor cell-specific death inducing cytokine which induces apoptosis through activating the extrinsic apoptosis pathway. A recent study has demonstrated that TRAIL enhances PI-induced apoptosis by helping initiate a positive feedback mechanism leading to Mcl-1 protein cleavage in some lung cancer cells. To enhance PI-induced apoptosis in MPM cells, we investigated the effect of TRAIL (10-20 ng/ml) and PI (MG132, 0.5-1 \#956;M) combination treatment. It was found that TRAIL and PI co-treatment induced a much more significant apoptosis, as was measured by cell viability, DNA damage and protein cleavages, than treatment with either single agent alone in MPM cell lines NCI-H2452, NCI-H2052 and NCI-H28. Using caspase specific inhibitors, we further found that activation of both the intrinsic and extrinsic apoptosis pathways contributed to the combination treatment-induced apoptosis. Moreover, it was found that such apoptosis induction was governed by a positive feedback mechanism which enhanced caspase activations and induced Mcl-1 protein cleavage leading to ensured cell death. Most importantly, we observed that the combination treatment exhibited a preferential toxicity to MPM cells rather than to non-tumorigenic Met-5A mesothelial cells. We thus conclude that TRAIL enhances PI-induced apoptosis in MPM cells through promoting the positive feedback mechanism-governed caspase activation and Mcl-1 protein cleavage. And, TRAIL and PI combination treatment may therefore represent a new effective therapy for treating MPMs.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 404.