叶酸通过 PI3K/AKT/mTOR 信号通路对 MNNG 诱导的食管上皮细胞增殖的保护作用

IF 4.8 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Journal of Nutritional Biochemistry Pub Date : 2024-07-16 DOI:10.1016/j.jnutbio.2024.109702
Suizhi Cheng , Jin Chen , Qianhui Li , Yuhong Nie , Ting Ni , Caiting Peng , Xi Luo , Pazilat Yasin , Shumin Zhang , Jiancai Tang , Zhenzhong Liu
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引用次数: 0

摘要

最近的研究发现,N-甲基-N′-亚硝基-N-亚硝基胍(MNNG)是食道癌发病的一个重要危险因素。一些研究阐明了叶酸(FA)在保护食管上皮细胞免受 MNNG 诱导的损伤方面的有益影响。因此,我们假设叶酸可通过干扰 PI3K/AKT/mTOR 信号通路来防止 MNNG 诱导的食管上皮细胞增殖。在体内实验中,我们发现 FA 可拮抗 MNNG 诱导的大鼠食管粘膜上皮棘细胞增殖和 PI3K/AKT/mTOR 信号通路的激活。在体外实验中,我们观察到急性暴露于 MNNG 24 小时后,永生化的人正常食管上皮细胞系(Het-1A)的增殖能力下降,PI3K/AKT/mTOR 信号通路受到抑制,而补充 FA 后情况也有所改善。我们通过暴露于 MNNG 诱导 Het-1A 细胞恶性转化,成功建立了 Het-1A-T 细胞系。值得注意的是,在这一转变过程中,PI3K/AKT2/mTOR 通路出现了先抑制后激活的现象。接着,我们观察到 FA 抑制了 Het-1A-T 恶性转化细胞的细胞增殖和 PI3K/AKT2/mTOR 信号通路的激活。我们进一步研究了 PI3K 激动剂 740Y-P 和 PI3K 抑制剂 LY294002 对 Het-1A-T 细胞增殖的影响。总之,我们的研究结果表明,补充足叶酸可减少 MNNG 诱导的 PI3K/AKT2/mTOR 信号通路的激活,从而有利于保护正常食管上皮细胞的增殖,避免食管癌的发生。
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Protective effect of folic acid on MNNG-induced proliferation of esophageal epithelial cells via the PI3K/AKT/mTOR signaling pathway

Recent research has revealed that N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) constitutes a significant risk factor in the development of esophageal cancer. Several investigations have elucidated the beneficial impact of folic acid (FA) in safeguarding esophageal epithelial cells against MNNG-induced damage. Therefore, we hypothesized that FA might prevent MNNG-induced proliferation of esophageal epithelial cells by interfering with the PI3K/AKT/mTOR signaling pathway. In vivo experiments, we found that FA antagonized MNNG-induced proliferation of rat esophageal mucosal epithelial echinocytes and activation of the PI3K/AKT/mTOR signaling pathway. In our in vitro experiments, it was observed that acute exposure to MNNG for 24 h led to a decrease in proliferative capacity and inhibition of the PI3K/AKT/mTOR signaling pathway in an immortalized human normal esophageal epithelial cell line (Het-1A), which was also ameliorated by supplementation with FA. We successfully established a Het-1A-T-cell line by inducing malignant transformation in Het-1A cells through exposure to MNNG. Notably, the PI3K/AKT2/mTOR pathway showed early suppression followed by activation during this transition. Next, we observed that FA inhibited cell proliferation and activation of the PI3K/AKT2/mTOR signaling pathway in Het-1A-T malignantly transformed cells. We further investigated the impact of 740Y-P, a PI3K agonist, and LY294002, a PI3K inhibitor, on Het-1A-T-cell proliferation. Overall, our findings show that FA supplementation may be beneficial in safeguarding normal esophageal epithelial cell proliferation and avoiding the development of esophageal cancer by decreasing the activation of the MNNG-induced PI3K/AKT2/mTOR signaling pathway.

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来源期刊
Journal of Nutritional Biochemistry
Journal of Nutritional Biochemistry 医学-生化与分子生物学
CiteScore
9.50
自引率
3.60%
发文量
237
审稿时长
68 days
期刊介绍: Devoted to advancements in nutritional sciences, The Journal of Nutritional Biochemistry presents experimental nutrition research as it relates to: biochemistry, molecular biology, toxicology, or physiology. Rigorous reviews by an international editorial board of distinguished scientists ensure publication of the most current and key research being conducted in nutrition at the cellular, animal and human level. In addition to its monthly features of critical reviews and research articles, The Journal of Nutritional Biochemistry also periodically publishes emerging issues, experimental methods, and other types of articles.
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