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Transcriptomic analysis of the effect of (E)-3-(3,5-dimethoxyphenyl)-1-(2-methoxyphenyl) prop-2-en-1-one (DPP23) on reactive oxygen species generation in MIA PaCa-2 pancreatic cancer cells

Genes & Genomics 2020년 42권 11호 p.1267 ~ 1279
심홍남, 정의택, 이다현, 최지혜, 이영한, 신순영,
소속 상세정보
심홍남 ( Sim Hong-Nam ) - Konkuk University Sanghuh College of Life Sciences Department of Biological Sciences
정의택 ( Jung Eui-Taek ) - Konkuk University Sanghuh College of Life Sciences Department of Biological Sciences
이다현 ( Lee Da-Hyun ) - Konkuk University Sanghuh College of Life Sciences Department of Biological Sciences
최지혜 ( Choi Ji-Hye ) - Konkuk University Sanghuh College of Life Sciences Department of Biological Sciences
이영한 ( Lee Young-Han ) - Konkuk University Sanghuh College of Life Sciences Department of Biological Sciences
신순영 ( Shin Soon-Young ) - Konkuk University Sanghuh College of Life Sciences Department of Biological Sciences

Abstract


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.

키워드

DPP23; ROS; Glutathione; CHAC1; Expression profiles

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