A prolyl-hydroxylase inhibitor, ethyl-3,4-dihydroxybenzoate, induces cell autophagy and apoptosis in esophageal squamous cell carcinoma cells via up-regulation of BNIP3 and N-myc downstream-regulated gene-1.
A prolyl-hydroxylase inhibitor, ethyl-3,4-dihydroxybenzoate, induces cell autophagy and apoptosis in esophageal squamous cell carcinoma cells via up-regulation of BNIP3 and N-myc downstream-regulated gene-1.
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脯氨酰羟化酶抑制剂 3,4-二羟基苯甲酸乙酯通过上调 BNIP3 和 N-myc 下游调节基因 1 诱导食管鳞状细胞癌细胞自噬和凋亡
DOI：
10.1371/journal.pone.0107204
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Zhao X
中科院分区：
文献类型：
--
作者：
Han B;Li W;Sun Y;Zhou L;Xu Y;Zhao X
原儿茶酸乙酯乙基-3，4-二羟基苯甲酸酯是在花生种子的种皮中发现的抗氧化剂。已有研究表明，3，4-二羟基苯甲酸乙酯可通过抑制脯氨酰羟化酶而有效降低乳腺癌细胞的转移。在这项研究中，我们研究了3，4-二羟基苯甲酸乙酯对食管鳞状细胞癌细胞的体外细胞毒性作用，并通过转录表达谱确定了3，4-二羟基苯甲酸乙酯诱导食管癌细胞死亡的关键调控因子。使用流式细胞仪分析，我们发现，乙基-3，4-二羟基苯甲酸酯诱导S期积累，线粒体膜透性的损失，和半胱天冬酶依赖的细胞凋亡。此外，表达谱分析鉴定了用乙基-3，4-二羟基苯甲酸酯处理的食管癌KYSE 170细胞中的46个上调和9个下调基因。这些差异表达的基因参与与细胞周期调控和细胞代谢相关的几种信号通路。与表达谱结果一致，通过逆转录PCR和蛋白质印迹分析发现候选基因NDRG 1、BNIP 3、AKR 1C 1、CCNG 2和VEGFA在处理的KYSE 170细胞中的转录和蛋白质表达水平显著增加。我们还发现缺氧诱导因子-1 α、BNIP 3、Beclin和NDRG 1的蛋白水平增加，并且BNIP 3和Beclin的富集表达引起经处理的细胞中微管相关蛋白1轻链3介导的自噬。食管癌细胞经3，4-二羟基苯甲酸乙酯作用后，自噬和凋亡同时被激活。此外，敲低NDRG 1表达的siRNA显着减弱了癌细胞的凋亡，这意味着NDRG 1可能是乙基-3，4-二羟基苯甲酸酯诱导的凋亡所必需的。总之，这些结果表明，3，4-二羟基苯甲酸乙酯的细胞毒性作用是通过上调NDRG 1、BNIP 3、Beclin和缺氧诱导因子-1 α介导的，在早期启动BNIP 3和Beclin介导的自噬，并最终导致食管癌细胞凋亡。
The protocatechuic acid ethyl ester ethyl-3,4-dihydroxybenzoate is an antioxidant found in the testa of peanut seeds. Previous studies have shown that ethyl-3,4-dihydroxybenzoate can effectively reduce breast cancer cell metastasis by inhibiting prolyl-hydroxylase. In this study, we investigated the cytotoxic effect of ethyl-3,4-dihydroxybenzoate on esophageal squamous cell carcinoma cells in vitro and identified key regulators of ethyl-3,4-dihydroxybenzoate-induced esophageal cancer cell death through transcription expression profiling. Using flow cytometry analysis, we found that ethyl-3,4-dihydroxybenzoate induced S phase accumulation, a loss in mitochondrial membrane permeabilization, and caspase-dependent apoptosis. Moreover, an expression profile analysis identified 46 up- and 9 down-regulated genes in esophageal cancer KYSE 170 cells treated with ethyl-3,4-dihydroxybenzoate. These differentially expressed genes are involved in several signaling pathways associated with cell cycle regulation and cellular metabolism. Consistent with the expression profile results, the transcriptional and protein expression levels of candidate genes NDRG1, BNIP3, AKR1C1, CCNG2 and VEGFA were found to be significantly increased in treated KYSE 170 cells by reverse-transcription PCR and western blot analysis. We also found that protein levels of hypoxia-inducible factor-1α, BNIP3, Beclin and NDRG1 were increased and that enriched expression of BNIP3 and Beclin caused autophagy mediated by microtubule-associated protein 1 light chain 3 in the treated cells. Autophagy and apoptosis were activated together in esophageal cancer cells after exposed to ethyl-3,4-dihydroxybenzoate. Furthermore, knock-down of NDRG1 expression by siRNA significantly attenuated apoptosis in the cancer cells, implying that NDRG1 may be required for ethyl-3,4-dihydroxybenzoate-induced apoptosis. Together, these results suggest that the cytotoxic effects of ethyl-3,4-dihydroxybenzoate were mediated by the up-regulation of NDRG1, BNIP3, Beclin and hypoxia-inducible factor-1α, initiating BNIP3 and Beclin mediated autophagy at an early stage and ultimately resulting in esophageal cancer cell apoptosis.
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影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
影响因子：
3.7
作者：
George J;Singh M;Srivastava AK;Bhui K;Roy P;Chaturvedi PK;Shukla Y
通讯作者：
Shukla Y
影响因子：
11.2
作者：
Gilkes DM;Chaturvedi P;Bajpai S;Wong CC;Wei H;Pitcairn S;Hubbi ME;Wirtz D;Semenza GL
通讯作者：
Semenza GL
影响因子：
5.6
作者：
Abubakar MB;Abdullah WZ;Sulaiman SA;Suen AB
通讯作者：
Suen AB
影响因子：
3.1
作者：
Li, Xuelei;Prescott, Mark;Devenish, Rodney J.
通讯作者：
Devenish, Rodney J.