Docosahexaenoic Acid Attenuates Bioenergetic Function and Inhibits Mammary Carcinoma Survival and Progression
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Breast cancer is the second leading cause of cancer-related mortality for women in the United States. Only 5-10 percent of diagnosed breast cancer cases are attributed to known hereditary factors, making breast cancer arguably an acquired disease. A major contributor to breast cancer incidence is diet. The glycolytic switch, known as the Warburg Effect, is observed in many malignant models and results in a unique metabolic shift in energy metabolism where tumor cells increase anaerobic glycolysis even in the presence of normal oxygen levels. The stabilization of the Warburg metabolic phenotype and malignant transformation is linked to the activities of two major contributing factors, hypoxia-inducible factor 1alpha (HIF-1alpha) and myelocytomatosis (Myc) oncogene. Together, HIF-1alpha and Myc induce a cascade of events that mediate changes in metabolism, cell signaling, proliferation, growth, and differentiation. The current study evaluated whether polyunsaturated fatty acids (PUFAs), specifically docosahexaenoic acid (DHA), could modify the malignant network coordinated by HIF-1alpha and Myc. Interestingly, DHA treatment in the breast cancer cell lines BT-474 and MDA-MB-231 decreased protein expression level and transcriptional activity of HIF-1alpha and suppressed cancer cell metabolism. Functional consequences of suppressing HIF-1alpha activity led to a significant inhibition of glucose metabolism by 50%. Glucose uptake, glucose usage through glycolysis, and total glucose oxidation were all depressed upon DHA supplementation. DHA decreased the oxygen consumption rates (OCR) and extracellular acidification rates (ECAR) as well as the bioenergetic profile of cancer cells. Moreover, cells treated with DHA had significant decreases in intracellular ATP levels, which induced phosphorylation of the metabolic stress marker AMP-activated protein kinase alpha (AMPKalpha) at Thr172. Increases in metabolic stress and oxidative stress also led to increased cellular apoptosis in cancer cells treated with DHA. Myc activity was found to be partially responsible for the induction of apoptosis in cancer cells, although the way in which apoptosis was activated was opposite between the two cancer cell lines, BT-474 and MDA-MB-231. Observations revealed that DHA supplementation in the BT-474 cell line stimulated total phosphorylation and transcriptional activity and induced apoptotic events involving Bcl-2-associated X protein (BAX), partially through a Myc-dependent mechanism. However, the MDA-MB-231 cells treated with DHA resulted in decreases in both Myc total phosphorylation and transcriptional activity. Similar to the BT-474 cell line, MDA-MB-231 cells treated with DHA resulted in decreases in proliferation and cell viability and increases in apoptosis, but Myc did not seem to be required. Taken together, the mechanisms by which DHA induces metabolic stress and apoptosis through targeting the function of HIF-1alpha and Myc activities contribute to the impaired growth and survival of malignant cell lines. These data provide rationale for clinical cancer intervention with DHA.