甲状腺激素诱导的炎症细胞因子表达干扰白藜芦醇对口腔癌细胞的抗增殖作用。
Thyroid hormone-induced expression of inflammatory cytokines interfere with resveratrol-induced anti-proliferation of oral cancer cells.
机构信息
Graduate Institute of Nanomedicine and Medical Engineering, College of Medical Engineering, Taipei Medical University, Taipei, 11031, Taiwan; Taipei Cancer Center, Taipei Medical University, Taipei, 11031, Taiwan.
Department of Pediatrics, E-Da Hospital, Kaohsiung, 82445, Taiwan; School of Medicine, I-Shou University, Kaohsiung, 84001, Taiwan.
出版信息
Food Chem Toxicol. 2019 Oct;132:110693. doi: 10.1016/j.fct.2019.110693. Epub 2019 Jul 20.
Thyroid hormone, L-thyroxine (T), induces inflammatory genes expressions and promotes cancer growth. It also induces expression of the checkpoint programmed death-ligand 1 (PD-L1), which plays a vital role in cancer progression. On the other hand, resveratrol inhibits inflammatory genes expressions. Moreover, resveratrol increases nuclear inducible cyclooxygenase (COX)-2 accumulation, complexes with p53, and induces p53-dependent anti-proliferation. In this study, we investigated the effect of T on resveratrol-induced anti-proliferation in oral cancer. T increased the expression and cytoplasmic accumulation of PD-L1. Increased expressions of pro-inflammatory genes, interleukin (IL)-1β and transforming growth factor (TGF)-β1, were shown to stimulate PD-L1 expression. T stimulated pro-inflammatory and proliferative genes expressions, and oral cancer cells proliferation. In contrast, resveratrol inhibited those genes and activated anti-proliferative genes. T retained resveratrol-induced COX-2 in cytoplasm and prevented COX-2 nuclear accumulation when resveratrol treated cancer cells. A specific signal transducer and activator of transcription 3 (STAT3) inhibitor, S31-201, blocked T-induced inhibition and restored resveratrol-induced nuclear COX-2 accumulation. By inhibiting the T-activated STAT3 signal transduction axis with S31-201, resveratrol was able to sequentially reestablish COX-2/p53-dependent gene expressions and anti-proliferation. These findings provide a novel understanding of the inhibitory effects of T on resveratrol-induced anticancer properties via the sequential expression of PD-L1 and inflammatory genes.
甲状腺激素，L-甲状腺素（T），诱导炎症基因表达并促进癌症生长。它还诱导检查点程序性死亡配体 1（PD-L1）的表达，这在癌症进展中起着至关重要的作用。另一方面，白藜芦醇抑制炎症基因的表达。此外，白藜芦醇增加核诱导型环氧化酶（COX）-2 的积累，与 p53 结合，并诱导 p53 依赖性抗增殖。在这项研究中，我们研究了 T 对口腔癌细胞中白藜芦醇诱导的抗增殖作用的影响。T 增加了 PD-L1 的表达和细胞质积累。促炎基因白细胞介素（IL）-1β和转化生长因子（TGF）-β1 的表达增加被证明能刺激 PD-L1 的表达。T 刺激促炎和增殖基因的表达，并刺激口腔癌细胞的增殖。相比之下，白藜芦醇抑制这些基因并激活抗增殖基因。当用白藜芦醇处理癌细胞时，T 将白藜芦醇诱导的 COX-2 保留在细胞质中并阻止 COX-2 的核积累。一种特定的信号转导和转录激活因子 3（STAT3）抑制剂 S31-201 阻断了 T 诱导的抑制作用，并恢复了白藜芦醇诱导的 COX-2 核积累。通过用 S31-201 抑制 T 激活的 STAT3 信号转导轴，白藜芦醇能够依次重建 COX-2/p53 依赖性基因表达和抗增殖作用。这些发现为 T 通过 PD-L1 和炎症基因的顺序表达对白藜芦醇诱导的抗癌特性的抑制作用提供了新的认识。
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