Transcriptomic Response of Breast Cancer Cells MDA-MB-231 to Docosahexaenoic Acid: Downregulation of Lipid and Cholesterol Metabolism Genes and Upregulation of Genes of the Pro-Apoptotic ER-Stress Pathway

Abstract

Despite considerable efforts in prevention and therapy, breast cancer remains a major public health concern worldwide. Numerous studies using breast cancer cell lines have shown the antiproliferative and pro-apoptotic effects of docosahexaenoic acid (DHA). Some studies have also demonstrated the inhibitory effect of DHA on the migration and invasion of breast cancer cells, making DHA a potential anti-metastatic agent. Thus, DHA has shown its potential as a chemotherapeutic adjuvant. However, the molecular mechanisms triggering DHA effects remain unclear, and the aim of this study was to provide a transcriptomic basis for further cellular and molecular investigations. Therefore, MDA-MB-231 cells were treated with 100 µM DHA for 12 h or 24 h before RNA-seq analysis. The results show the great impact of DHA-treatment on the transcriptome, especially after 24 h of treatment. The impact of DHA is particularly visible in genes involved in the cholesterol biosynthesis pathway that is strongly downregulated, and the endoplasmic reticulum (ER)-stress response that is, conversely, upregulated. This ER-stress and unfolded protein response could explain the pro-apoptotic effect of DHA. The expression of genes related to migration and invasion (especially SERPINE1, PLAT, and MMP11) is also impacted by DHA. In conclusion, this transcriptomic analysis supports the antiproliferative, pro-apoptotic and anti-invasive effects of DHA, and provides new avenues for understanding its molecular mechanisms.

Co-Administration of Propionate or Protocatechuic Acid Does Not Affect DHA-Specific Transcriptional Effects on Lipid Metabolism in Cultured Hepatic Cells

“…Our results emphasize that DHA effects are mediated, at least in part, by modulation of gene expression and clearly indicate that it mainly interferes with anabolic lipid metabolism primarily targeting the cholesterol synthesis pathway. The observed impact of DHA treatment on the transcriptome is in line with recently published results in breast cancer cells, where 100 µM DHA strongly downregulated genes involved in the cholesterol biosynthesis pathway, especially after 24 h of treatment [46]. Of note, a strong transcriptional component in the repression of SREBP1 activity was observed, suggesting that the control of nSREBP-1 abundance by DHA is not solely at the post-translational level.…”

Effects of Dietary n–3 and n–6 Polyunsaturated Fatty Acids in Inflammation and Cancerogenesis

“…The mechanisms of ER-dependent DHA-mediated antiproliferative and proapoptotic in breast cancer cells were confirmed by Chénais et al (2020). The results of their study confirmed that DHA mediates strong ER-stress response in MDA-MB-231, which was confirmed by the upregulation of numerous genes involved in heat shock and ROS stress and ER-stress induced apoptosis [127]. In another study, MDA-MB-231 breast cancer cells supplemented with DHA displayed an increased caspase-1 and gasdermin D activation, enhanced IL-1β secretion.…”

“…According to the authors, those effects were dependent on the increased ROS production from the intensified β-oxidation and oxidative phosphorylation in cancerous cells as a result of a metabolic switch caused by n-3 PUFA [126]. The mechanisms of ER-dependent DHA-mediated antiproliferative and proapoptotic in breast cancer cells were confirmed by Chénais et al (2020). The results of their study confirmed that DHA mediates strong ER-stress response in MDA-MB-231, which was confirmed by the upregulation of numerous genes involved in heat shock and ROS stress and ER-stress induced apoptosis [127].…”

“…Novel mechanisms of DHA and its metabolite resolvin D1 (RvD1) on cancer cell growth and invasion were described by Bai et al (2019) [159]. Moreover, DHA decreases MDA-MB-231 cells' invasiveness via upregulation of SERPINE1 and downregulation of PLAT and MMP11 genes [127].…”

2-Hydroxypropyl-β-cyclodextrin Regulates the Epithelial to Mesenchymal Transition in Breast Cancer Cells by Modulating Cholesterol Homeostasis and Endoplasmic Reticulum Stress

“…In this process, epithelial cells lose their differentiation characteristics and become mesenchymal cells, acquiring migratory and invasive abilities [ 14 ]. Breast cancer is the most frequently diagnosed cancer in women worldwide, and more than 90% of breast cancer deaths are related to tumor metastasis [ 15 , 16 ]. According to previous research, unlike in most other cancer cells, ER stress can block EMT in breast cancer cells [ 17 ].…”