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首页> 外文期刊>Journal of biochemical and molecular toxicology >Inhibition of NF-κB is required for oleanolic acid to downregulate PD-L1 by promoting DNA demethylation in gastric cancer cells
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Inhibition of NF-κB is required for oleanolic acid to downregulate PD-L1 by promoting DNA demethylation in gastric cancer cells

机译：通过促进胃癌细胞中的DNA去甲基化，葡聚糖酸需要抑制NF-κB。

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Gastric cancer is one of the most common causes of cancer-related death worldwide. Immunotherapy via programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) blockade has shown benefits for gastric cancer. Epigenetic DNA methylation critically regulates cancer immune checkpoints. We investigated how the natural compound oleanolic acid (OA) affected PD-L1 expression in gastric cancer cells. lnterleukin-1β (IL-1β) at 20ng/mL was used to stimulate human gastric cancer MKN-45 cells. IL-1β significantly increased PD-L1 expression, which was abolished by OA. Next, OA-treated MKN-45 cells were co-cultured with activated and PD-1-overexpressing Jurkat T cells. OA restored IL-2 levels in the co-culture system and increased T cell killing toward MKN-45 cells. Overexpression of PD-L1 eliminated OA-enhanced T cell killing capacity; however, PD-1 blocking antibody abrogated the cytotoxicity of T cells. Moreover, OA abolished IL-1β-increased DNA demethylase activity in MKN-45 cells. DNA me-thyltransferase inhibitor 5-azacytidine rescued OA-reduced PD-L1 expression; whereas DNA demethylation inhibitor gemcitabine inhibited PD-L1 expression, and, in combination with OA, provided more potent inhibitory effects. Furthermore, OA selectively reduced the expression of DNA demethylase TET3 in IL-1β-treated MKN-45 cells, and overexpression of TET3 restored OA-reduced PD-L1 expression. Finally, OA disrupted nuclear factor κB (NF-κB) signaling IL-1β-treated MKN-45 cells, and overexpression of NF-κB restored OA downregulation of TET3 and PD-L1. The cytotoxicity of T cells toward MKN-45 cells was also weakened by NF-κB overexpression. Altogether, OA blocked the IL-1β/NF-κB/TET3 axis in gastric cancer cells, leading to DNA hypomethylation and downregulation of PD-L1. Our discoveries suggested OA as an epigenetic modulator for immunotherapy or an adjuvant therapy against gastric cancer.
机译：胃癌是全世界最常见的癌症相关死亡原因之一。通过程序性细胞死亡蛋白1（PD-1）/程序性细胞死亡配体1（PD-L1）阻断进行免疫治疗已显示出对胃癌的益处。表观遗传DNA甲基化严重调节癌症免疫检查点。我们研究了天然化合物齐墩果酸（OA）对胃癌细胞PD-L1表达的影响。用20ng/mL的白细胞介素-1β（IL-1β）刺激人胃癌MKN-45细胞。IL-1β显著增加PD-L1表达，OA可消除PD-L1表达。接下来，将经OA处理的MKN-45细胞与活化和PD-1过度表达的Jurkat T细胞共同培养。OA恢复了共培养系统中的IL-2水平，并增加了对MKN-45细胞的T细胞杀伤。PD-L1的过度表达消除了OA增强的T细胞杀伤能力；然而，PD-1阻断抗体消除了T细胞的细胞毒性。此外，OA消除了IL-1β，提高了MKN-45细胞的DNA去甲基化酶活性。DNA甲基转移酶抑制剂5-氮杂胞苷降低PD-L1表达；而DNA去甲基化抑制剂吉西他滨抑制PD-L1的表达，并与OA联合使用，提供更有效的抑制作用。此外，OA选择性降低IL-1β处理的MKN-45细胞中DNA去甲基化酶TET3的表达，TET3的过度表达恢复了OA降低的PD-L1表达。最后，OA破坏了IL-1β处理的MKN-45细胞的核因子κB（NF-κB）信号传导，NF-κB的过度表达恢复了OA对TET3和PD-L1的下调。NF-κB过度表达也削弱了T细胞对MKN-45细胞的细胞毒性。总之，OA阻断了胃癌细胞中的IL-1β/NF-κB/TET3轴，导致DNA低甲基化和PD-L1的下调。我们的发现提示OA是一种表观遗传调节剂，用于免疫治疗或胃癌的辅助治疗。

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