Imperatorin Targets Mcl-1 To Sensitize Cd133(+) Lung Cancer Cells To Gamma Delta-T Cell-Mediated Cytotoxicity

Background/Aims: CD133(+) cancer cells display low sensitivity to anti-cancer treatment; thus, combination treatment with adjuvant drugs is required to improve the efficiency of cancer therapy. The aim of this study was to explore the effect of imperatorin, a linear furanocoumarin compound, on gamma delta T cell-mediated cytotoxicity against CD133(+) lung cancer cells. Methods: CD133(+) and CD133(-) subgroups from A549 and PC9 lung cancer cells were sorted by using flow cytometry. The cytotoxicity of gamma delta T cells against cancer cells was evaluated by measuring lactate dehydrogenase release. The concentration of tumor necrosis factor-related apoptosis-inducing ligand in the co-culture system was determined by using an enzyme-linked immunosorbent assay. Mitochondrial membrane potential, expression of death receptor 4 (DR4) and DR5 on the cell surface, and rate of apoptosis were measured by flow cytometry. Cytochrome c release and cellular protein expression were detected by western blot analysis. Results: Compared with CD133(-) cells, CD133(+) cells were resistant to gamma delta T cell-mediated cytotoxicity. However, imperatorin significantly increased the sensitivity of CD133(+) lung cancer cells to gamma delta T cell treatment in vitro and in vivo. Mechanically, we found that myeloid cell leukemia 1 (MCL-1), an important anti-apoptotic protein belonging to the Bcl-2 family, was overexpressed in CD133(+) A549 and PC9 cells compared to their corresponding CD133(-) cells. Co-treatment with imperatorin and gamma delta T cells suppressed the expression of MCL-1, and thus promoted the mitochondrial apoptosis mediated by gamma delta T cells in CD133(+) A549 and PC9 lung cancer cells. Conclusion: Up-regulated MCL-1 in CD133(+) lung cancer cells is responsible for their resistance to gamma delta T cells. Furthermore, the combination of gamma delta T cells with imperatorin sensitized CD133(+) lung cancer cells to gamma delta T cell-mediated cytotoxicity by targeting MCL-1. (C) 2018 The Author(s) Published by S. Karger AG, Basel