Imperatorin Targets MCL-1 to Sensitize CD133+ Lung Cancer Cells to γδ-T Cell-Mediated Cytotoxicity

Abstract

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 γδ 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 γδ 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 γδ T cell-mediated cytotoxicity. However, imperatorin significantly increased the sensitivity of CD133⁺ lung cancer cells to γδ 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 γδ T cells suppressed the expression of MCL-1, and thus promoted the mitochondrial apoptosis mediated by γδ 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 γδ T cells. Furthermore, the combination of γδ T cells with imperatorin sensitized CD133⁺ lung cancer cells to γδ T cell-mediated cytotoxicity by targeting MCL-1.

Imperatorin Positively Regulates Melanogenesis through Signaling Pathways Involving PKA/CREB, ERK, AKT, and GSK3β/β-Catenin

“…Imperatorin, known as ammidin, marmelide, and marmelosin, is a naturally occurring active furocoumarin and phytochemical that is mainly found in citrus fruits (such as Citrus grandis and Citrus maxima ) and some species of the genus Angelica that are used as medicine (such as Angelica biserrate , Angelica dahurica , Angelica archangelica , Angelica pubescens and Angelica albicans ). It is known to exert many pharmacological properties, including anti-inflammatory effects on inflammation-associated lung, liver, osteoarthritis, ulcerative colitis, and neuro diseases [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ] as well as anticancer [ 21 , 22 , 23 , 24 ] and antiviral activities [ 25 , 26 , 27 ]. A recent study has shown that imperatorin IMP can ameliorate PS-induced learning and memory deficits through the BDNF/TrkB and ERK/CaMKIIα/CREB signaling pathways and the hypothalamic–pituitary–adrenal axis [ 28 ].…”

A Mechanism Exploration for the Yi‐Fei‐San‐Jie Formula against Non‐Small‐Cell Lung Cancer Based on UPLC‐MS/MS, Network Pharmacology, and In Silico Verification

“…Finally, molecular docking and dynamics simulations validated the hypothesis that YFSJF inhibits PIK3R1, PIK3CA, and AKT1 to suppress the PI3K/ AKT pathway and fght NSCLC. After further literature review, it was found that the antitumor role of hub chemicals has been reported by many researchers, especially for lung cancer [54][55][56][57][58][59]. For instance, ginsenoside compound K, the major intestinal bacterial metabolite of ginsenoside Rb1, can induce apoptosis and autophagy in NSCLC cells by regulating the AMPK/mTOR pathway [54].…”

“…After further literature review, it was found that the antitumor role of hub chemicals has been reported by many researchers, especially for lung cancer [54][55][56][57][58][59]. For instance, ginsenoside compound K, the major intestinal bacterial metabolite of ginsenoside Rb1, can induce apoptosis and autophagy in NSCLC cells by regulating the AMPK/mTOR pathway [54]. Naringenin can induce Bax-mediated mitochondrial apoptosis in human lung adenocarcinoma A549 cells [55].…”

Anti-Cancer Activity of Phytochemicals Targeting Hypoxia-Inducible Factor-1 Alpha

“…Imperatorin was recognized to suppress cancer by halting cell cycle progression [ 145 ]. Moreover, imperatorin can augment the cytotoxicity of gamma-delta T cells against CD133-positive cancer via targeting myeloid cell leukemia 1 ( MCL1 ), an endogenous apoptosis inhibitor [ 146 ]. It was further shown that imperatorin inhibits TGF-β-mediated ERK activation, thus hindering metastasis [ 147 ].…”