Abstract 5430: Docosahexaenoic acid attenuates glycolytic metabolism and the Warburg phenotype by targeting hypoxia inducible factor 1 alpha in breast cancer.

Abstract

Abstract Dietary factors have been estimated to account for approximately 30-40 percent of cancer incidence and research has shown that high fat diets rich in n-3 polyunsaturated fatty acids (PUFAs) are associated with lower cancer occurrences, including breast cancer. The glycolytic switch, known as the Warburg Effect, is observed in many malignant models, which results in a unique metabolic shift in energy metabolism where tumor cells increase anaerobic glycolysis even in the presence of normal oxygen levels. In our laboratory, we have shown that the n-3 PUFA, docosahexaenoic acid (DHA; C22:6), significantly decreases total cellular ATP and the transcriptional activity and protein levels of hypoxia-inducible factor 1 alpha (HIF-1α), a major contributor to the Warburg phenotype. In this project, we set out to determine if DHA is responsible for attenuating the Warburg Effect through a HIF-1α-dependent mechanism. Alterations in glucose uptake and usage upon supplementation with DHA were examined in vitro in the breast cancer BT-474, MDA-MB-231, and non-transformed MCF-10A cell lines. Total glucose transporter 1 (GLUT 1) protein levels were determined in each cell line. No change was seen upon DHA supplementation in the MDA-MB-231 cell line, which may be due to overexpression of GLUT 1. However, GLUT 1 protein levels were significantly down in response to DHA treatment in the BT-474 cell line. We also observed significant decreases in glucose consumption through glycolysis and lactate production in the BT-474 and MDA-MB-231 cell lines upon DHA supplementation. However, no change was seen in the non-transformed cell line MCF-10A, suggesting that DHA is having anti-glucose-metabolism effects specifically on cancer cells, but not on non-transformed cells. Moreover, HIF-1α small interfering RNA (siRNA) experiments showed a similar trend in GLUT 1 expression and glycolytic capacity in the BT-474 and MDA-MB-231 cell lines, suggesting that DHA is exerting some of its anti-cancer effects through HIF-1α. Based on these findings, changes in glucose transporter expression and glucose usage likely contribute to the impaired growth and survival of malignant cell lines supplemented with DHA. Currently, therapies are being developed to target the Warburg Effect in the treatment of cancer and DHA could likely enhance such therapies. Citation Format: Michael Mouradian, Keith D. Kikawa, Ronald S. Pardini. Docosahexaenoic acid attenuates glycolytic metabolism and the Warburg phenotype by targeting hypoxia inducible factor 1 alpha in breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5430. doi:10.1158/1538-7445.AM2013-5430