Background

Reactive oxygen species (ROS) generation specifically in cancer cells may be a promising strategy for their selective killing. The synthetic chalcone derivative (E)-3-(3,5-dimethoxyphenyl)-1-(2-methoxyphenyl)prop-2-en-1-one (DPP23) exerts antitumor activity through ROS-mediated apoptosis in cancer cells but not in healthy cells. However, the mechanism underlying ROS generation by DPP23 remains unknown.

Objective

The current study aims to identify possible DPP23 target genes responsible for ROS generation through the mining of microarray data stored in NCBI's Gene Expression Omnibus (GEO).

Methods

A comprehensive expression profile of genes modulated by DPP23 was examined by gene ontology analysis. DPP23-modulated genes in Mia-PaCa2 pancreatic cells were validated by reverse transcription-PCR.

Results

Multiple genes were up and downregulated by DPP23 treatment in MiaPaCa2 pancreatic cancer cells. Genes with absolute fold-change (FC) of > 2 were selected as the cut-off criteria and grouped into 10 clusters to analyze expression patterns systematically. We observed that genes with increased expression at 6 h were significantly affected by ROS increase, unfolded protein response, and cell death. Expression of 13 genes involved in glutathione metabolism, including CHAC1, GCLC, G6PD, GSTO2, GSTA5, GSTM2, GSR, GPX3/6/8, GGT1, PGD, ATF4, and NAT8B, are modulated by DPP23. Of these, CHAC1 was most highly upregulated upon DPP23 treatment.

Conclusion

DPP23 alters global gene expression associated with multiple cellular responses, including oxidative stress and apoptosis. We found that DPP23 may induce GSH depletion through modulation of gene expression, which is especially involved in glutathione metabolism. Of these, CHAC1 emerged as the most prominent candidate for DPP23 as it was the most responsive to DPP23 treatment.

中文翻译：

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(E)-3-(3,5-二甲氧基苯基)-1-(2-甲氧基苯基) prop-2-en-1-one (DPP23) 对 MIA PaCa-2 胰腺中活性氧生成的影响的转录组学分析癌细胞。

背景

特别是在癌细胞中产生活性氧 (ROS) 可能是一种有前途的选择性杀伤策略。合成查尔酮衍生物 (E)-3-(3,5-二甲氧基苯基)-1-(2-甲氧基苯基)prop-2-en-1-one (DPP23) 通过 ROS 介导的癌细胞凋亡发挥抗肿瘤活性，但不在健康细胞中。然而，DPP23 产生 ROS 的机制仍然未知。

客观的

目前的研究旨在通过挖掘存储在 NCBI 的基因表达综合 (GEO) 中的微阵列数据来确定可能负责 ROS 生成的 DPP23 靶基因。

方法

通过基因本体分析检查了由 DPP23 调节的基因的综合表达谱。Mia-PaCa2 胰腺细胞中的 DPP23 调节基因通过逆转录 PCR 进行验证。

结果

在 MiaPaCa2 胰腺癌细胞中，多个基因被 DPP23 处理上调和下调。选择绝对倍数变化 (FC) > 2 的基因作为截止标准，并将其分为 10 个簇以系统地分析表达模式。我们观察到在 6 小时时表达增加的基因受到 ROS 增加、未折叠蛋白反应和细胞死亡的显着影响。的参与谷胱甘肽代谢13个基因，包括表达CHAC1，GCLC，G6PD，GSTO2，GSTA5，GSTM2，GSR，GPX3 / 6/8，GGT1，PGD，ATF4，和NAT8B，通过DPP23调制。其中，CHAC1在 DPP23 处理后最高度上调。

结论

DPP23 改变与多种细胞反应相关的全局基因表达，包括氧化应激和细胞凋亡。我们发现 DPP23 可能通过调节基因表达来诱导 GSH 耗竭，这尤其与谷胱甘肽代谢有关。其中，CHAC1成为DPP23最突出的候选者，因为它对 DPP23 治疗最敏感。