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.