Center for Genomics, Helmy Institute for Medical Sciences, Zewail City of Science and Technology, Giza 12578, Egypt.
Department of Pharmaceutical Biology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt.
Genes (Basel). 2023 Jan 5;14(1):144. doi: 10.3390/genes14010144.
The DNA Damage Response (DDR) pathways sense DNA damage and coordinate robust DNA repair and bypass mechanisms. A series of repair proteins are recruited depending on the type of breaks and lesions to ensure overall survival. An increase in glucose levels was shown to induce genome instability, yet the links between DDR and glucose are still not well investigated. In this study, we aimed to identify dysregulation in the transcriptome of normal and cancerous breast cell lines upon changing glucose levels. We first performed bioinformatics analysis using a microarray dataset containing the triple-negative breast cancer (TNBC) MDA-MB-231 and the normal human mammary epithelium MCF10A cell lines grown in high glucose (HG) or in the presence of the glycolysis inhibitor 2-deoxyglucose (2DG). Interestingly, multiple DDR genes were significantly upregulated in both cell lines grown in HG. In the wet lab, we remarkably found that HG results in severe DNA damage to TNBC cells as observed using the comet assay. In addition, several DDR genes were confirmed to be upregulated using qPCR analysis in the same cell line. Our results propose a strong need for DDR pathways in the presence of HG to oppose the severe DNA damage induced in cells.
DNA 损伤反应 (DDR) 途径感知 DNA 损伤，并协调强大的 DNA 修复和旁路机制。根据断裂和损伤的类型，会募集一系列修复蛋白，以确保整体存活。研究表明，葡萄糖水平的升高会导致基因组不稳定，但 DDR 与葡萄糖之间的联系仍未得到充分研究。在这项研究中，我们旨在确定改变葡萄糖水平后正常和癌细胞系转录组的失调。我们首先使用包含三阴性乳腺癌 (TNBC) MDA-MB-231 和正常人类乳腺上皮 MCF10A 细胞系在高葡萄糖 (HG) 或糖酵解抑制剂 2-脱氧葡萄糖 (2DG) 存在下生长的微阵列数据集进行生物信息学分析。有趣的是，HG 培养的两种细胞系中多个 DDR 基因显著上调。在湿实验室中，我们使用彗星试验显著发现 HG 导致 TNBC 细胞严重的 DNA 损伤。此外，在同一细胞系中使用 qPCR 分析证实了几个 DDR 基因的上调。我们的结果表明，在 HG 存在下，DDR 途径强烈需要对抗细胞中诱导的严重 DNA 损伤。
