Abstract 1864: Mitochondrial bioenergetics of metastatic breast cancer cells in response to decreasing oxygen tension.

Abstract

Abstract Solid tumors are characterized by regions of low oxygen tension, which play a central role in tumor progression and resistance to therapy. The major organelle affected by reduced oxygen tension is the mitochondrion, which has to functionally adapt to maintain cellular bioenergetics for the cell survival. In the present study, a novel experimental approach was developed to examine the real-time bioenergetic changes during adaptation to various oxygen tensions ranging from 20% to < 1% oxygen using highly sensitive extracellular flux technology. Oxygen was gradually removed from the culture medium, and bioenergetic changes were measured in normal breast epithelial (MCF10A) and metastatic cancer cell lines (MDA-MB-231 and MCF10CA clones). We found that breast cancer cells, but not MCF10A cells, rapidly responded to low oxygen tension by stabilizing HIF-1α, increasing hypoxia responsive gene expression, and stimulating cellular uptake of glucose, confirming previous observations. In addition, breast cancer cells increased extracellular acidification rate (ECAR) or glycolysis during adaptation to low oxygen tension, and this effect was markedly lower in MCF10A cells. Interestingly, breast cancer cells exhibited a biphasic response in oxygen consumption rate (OCR) as the oxygen tension was reduced gradually from 20% to <1.0%, a response not previously described. This effect is HIF-1α-dependent, as silencing HIF-1α function in cancer cells completely abolished the biphasic response in OCR and increase in ECAR. Moreover, cancer cells demonstrated the ability to restore and maintain its OCR steadily at specific oxygen tension either during deoxygenation or reoxygenation, an effect not observed in HIF-1α silenced cells. Additional studies confirmed that the initial stimulation of OCR is due to increased mitochondrial respiration. In conclusion, our results suggest that HIF-1α provides high degree of bioenergetic flexibility under different oxygen tensions which may confer an adaptive advantage in the ever-changing tumor microenvironment as well as during invasion and metastasis. Moreover, these differences may be useful in screening novel therapeutic agents that target the bioenergetics of cancer cells in response to low oxygen tension. Citation Format: Praveen K. Vayalil, Anne R. Diers, Claudia R. Olivia, Corinne E. Griguer, Victor Darley-Usmar, Douglas R. Hurst, Danny R. Welch, Aimee Landar. Mitochondrial bioenergetics of metastatic breast cancer cells in response to decreasing oxygen tension. [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 1864. doi:10.1158/1538-7445.AM2013-1864