Flavonoid 4,4′-dimethoxychalcone suppresses cell proliferation via dehydrogenase inhibition and oxidative stress aggravation
Flavonoid 4,4′-dimethoxychalcone suppresses cell proliferation via dehydrogenase inhibition and oxidative stress aggravation
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类黄酮4,4α-二甲氧基查耳酮通过抑制脱氢酶和加剧氧化应激来抑制细胞增殖
DOI：
10.1016/j.freeradbiomed.2021.09.002
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发表时间：
2021-09-10
影响因子：
7.4
通讯作者：
Deng, Haiteng
中科院分区：
文献类型：
--
作者：
Yang, Changmei;Zhu, Songbiao;Deng, Haiteng
黄酮类化合物是一类具有多种生物活性和保健作用的天然多酚类化合物。最近的研究发现，4，4 '-二甲氧基查耳酮（DMC）通过自噬促进长寿;然而，其靶点目前尚不清楚。在此，我们采用了无偏热蛋白质组分析（TPP）方法，并确定了DMC的多个目标，包括ALDH 1A 3，ALDH 2和PTGES 2。我们进一步使用微型热泳（MST）分析确定DMC和ALDH 1A 3的解离常数（Kd）为2.8 μ M，这表明DMC抑制ALDH 1A 3活性并加剧细胞氧化应激。DMC治疗显著增加细胞活性氧（ROS）的产生，并抑制癌细胞生长。定量蛋白质组学分析表明，DMC上调与应激反应相关的蛋白质，下调与细胞周期进程相关的蛋白质，这是使用细胞周期分析证实。总之，我们表明TPP是一种有效的工具，可以用来识别类黄酮的目标，并为未来破译类黄酮的功能奠定了先例。我们已经证明DMC通过ROS诱导的细胞周期阻滞抑制细胞增殖，并且是癌症治疗中的抗增殖剂。
Flavonoids are natural polyphenolic compounds with a diverse array of biological activities and healthpromoting effects. Recent studies have found that 4,4'-dimethoxychalcone (DMC) promoted longevity via autophagy; however, its targets are currently unknown. Herein, we employed an unbiased thermal proteome profiling (TPP) method and identified multiple targets of DMC, including ALDH1A3, ALDH2, and PTGES2. We further determined the dissociation constant (Kd) of DMC and ALDH1A3 to be 2.8 mu M using microscale thermophoresis (MST) analysis, which indicated that DMC inhibited ALDH1A3 activity and aggravated cellular oxidative stress. DMC treatment significantly increased cellular reactive oxygen species (ROS) production and inhibited cancer cell growth. Quantitative proteomic analysis showed that DMC upregulated proteins associated with stress-responses and downregulated proteins associated with cell cycle progression, and this was confirmed using cell cycle analysis. Taken together, we showed that TPP is an effective tool with which to identify flavonoid targets and set a precedent for deciphering flavonoid function in the future. We have demonstrated that DMC inhibited cell proliferation via ROS-induced cell cycle arrest and is an anti-proliferative agent in cancer treatment.