Docosahexaenoic acid attenuates breast cancer cell metabolism and the Warburg phenotype by targeting bioenergetic function

Abstract

Docosahexaenoic acid (DHA; C22:6n-3) depresses mammary carcinoma proliferation and growth in cell culture and in animal models. The current study explored the role of interrupting bioenergetic pathways in BT-474 and MDA-MB-231 breast cancer cell lines representing respiratory and glycolytic phenotypes, respectively and comparing the impacts of DHA with a non-transformed cell line, MCF-10A. Metabolic investigation revealed that DHA supplementation significantly diminished the bioenergetic profile of the malignant cell lines in a dose-dependent manner. DHA enrichment also resulted in decreases in hypoxia-inducible factor (HIF-1α) total protein level and transcriptional activity in the malignant cell lines but not in the non-transformed cell line. Downstream targets of HIF-1α, including glucose transporter 1 (GLUT 1) and lactate dehydrogenase (LDH), were decreased by DHA treatment in the BT-474 cell line, as well as decreases in LDH protein level in the MDA-MB-231 cell line. Glucose uptake, total glucose oxidation, glycolytic metabolism, and lactate production were significantly decreased in response to DHA supplementation; thereby enhancing metabolic injury and decreasing oxidative metabolism. The DHA-induced metabolic changes led to a marked decrease of intracellular ATP levels by 50% in both cancer cell lines, which mediated phosphorylation of metabolic stress marker, AMPK, at Thr172. These findings show that DHA contributes to impaired cancer cell growth and survival by altering cancer cell metabolism, increasing metabolic stress and altering HIF-1α-associated metabolism, while not affecting non-transformed MCF-10A cells. This study provides rationale for enhancement of current cancer prevention models and current therapies by combining them with dietary sources, like DHA.

Analysis and Interpretation of Microplate-Based Oxygen Consumption and pH Data

“…A bulk of these comparisons have been made in models of cancer (Blouin et al, 2010;Chan et al, 2011;Delgado et al, 2010;Frezza et al, 2011;Liu et al, 2014;Mouradian et al, 2014;Xie et al, 2009). A bulk of these comparisons have been made in models of cancer (Blouin et al, 2010;Chan et al, 2011;Delgado et al, 2010;Frezza et al, 2011;Liu et al, 2014;Mouradian et al, 2014;Xie et al, 2009).…”

Docosahexaenoic acid attenuates the detrimental effect of palmitic acid on human endothelial cells by modulating genes from the atherosclerosis signaling pathway

“…25 For induction of atherosclerosis, saturated fatty acids, notably Pal, were used extensively in vitro. Until now, the potential therapeutic activity of various concentrations of DHA was investigated on distinct cell types.…”

“…25 In short, 200 µL DMEM/F12 medium with 1 × 10 4 HUVECs was plated in each well of a 96-well plate (SPL). 25 In short, 200 µL DMEM/F12 medium with 1 × 10 4 HUVECs was plated in each well of a 96-well plate (SPL).…”

“…We investigated the different concentrations of DHA, including 1.25, 2.5, 5, 10, 20, 40, and 80 µM for 24 hours. 25 In short, 200 µL DMEM/F12 medium with 1 × 10 4 HUVECs was plated in each well of a 96-well plate (SPL). Once the incubation time was complete, 50 µL MTT solution (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide [5 mg/mL, Cat no: M5655; Sigma-Aldrich, St. Louis, MO]) was added into each well and incubated for 4 hours.…”

Investigation into the distinct subcellular effects of docosahexaenoic acid loaded low-density lipoprotein nanoparticles in normal and malignant murine liver cells

“…Dysregulation of each of these additional organelle systems contribute to the trauma sustained by the cancer cells. In addition, alterations in mitogenic signaling (suppression of β-catenin [67], HIF1α [68], NFκB [69], etc.) have also been attributed to DHA; collectively, all these disturbances act to ultimately usher in the demise of the cancer cell.…”