TRAIL and proteasome inhibitors combination induces a robust apoptosis in human malignant pleural mesothelioma cells through Mcl-1 and Akt protein cleavages

Bao-Zhu Yuan,Junzhi Wang,Binghua Jiang,Joshua Chapman,Steven H Reynolds,Yon Rojanasakul,Min Ding

doi:10.1186/1471-2407-13-140

Abstract

BackgroundMalignant 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.MethodsProteasome inhibitors (PIs) and TNFα-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.ResultsTreatment with 0.5-1 μM 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.ConclusionThe combinatorial treatment using TRAIL and PI may represent an effective new treatment for MPMs.

Highlights

Malignant pleural mesothelioma (MPM) is an aggressive malignancy closely associated with asbestos exposure and extremely resistant to current treatments
Chemicals: proteasome inhibitor MG132, caspase inhibitors for wide spectrum caspases (Z-VAD-fmk), caspase 3 (Z-DQMD-fmk), caspase 8 (Z-IETD-fmk), caspase 9 (Z-LEHD-fmk) and caspase 10 (Z-AEVD-fmk), and a negative control (ZFA-fmk), PI3K specific inhibitor LY294002, were from EMD-CalBiochem (San Diego, CA); proteasome inhibitor Bortezomid was from ChemieTek (Indianapolis, IN); Mcl-1 siRNA and a negative control siRNA were from Santa Cruz (Santa Cruz, CA); Soluble recombinant human TNFα-Related Apoptosis Inducing Ligand (TRAIL) protein was from R&D Systems (Minneapolis, MN)
Proteasome inhibitor MG132 alone or TRAIL alone induces a limited apoptosis in MPM cells In this study, we observed that 0.5-1 μM MG132 induced only a limited cell death and protein cleavages in both NCI-H2452 and NCI-H2052 cells with a greater effect seen in NCI-H2452 cells, but no effects in NCI-H28 cells (Figure 1A & B)

Summary

Introduction

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, necessitating an urgent development of effective new treatments. MPM is extremely resistant to most chemotherapy regimens examined and not responsive primarily to radiation therapy in general [3,4]. Recent clinical studies showed that tri-modality therapy with radical pleurectomy, chemotherapy with cisplatin plus pemetrexed or cisplatin plus gemcitabine, and radiation can significantly increase median survival rate of MPM patients up to 30 months from previously less than 12 months with mono-therapy [7,8]. It is still urgent to search for effective new treatments for MPM

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