May 8-13, 2016
Metabolism plays a critical role in the progression of cancer malignancy, with nutrient source flexibility allowing cancer cells to outcompete normal cells and survive harsh environmental conditions. Lactate accumulation in poorly vascularized tumors has predominately been considered a waste product resulting from the Warburg effect; however, recent studies have shown that lactate can additionally serve as a metabolic substrate for some cancer cells, a process referred to as the Reverse Warburg effect. Lactate accumulation is also associated with cancer stem cell-like gene expression, drug-resistance, metastasis, and poor prognosis in breast cancer patients. Unfortunately, little is known about the role of lactate in cancer cell metabolism and progression. This study examined the impact of extracellular lactate on the metabolic activity of normal breast cells (MCF-10A), early stage breast cancer cells (MCF-7), and advanced, malignant breast cancer cells (MDA-MB-231) by utilizing steady-state 13C-metabolic flux analysis. To quantify individual metabolic pathway activity, metabolic flux maps were constructed for each cell line for both control and high lactate conditions. Cellular composition studies were performed to determine the effect of high lactate on cellular amino acid composition and lipid content. The high lactate condition resulted in altered cell metabolism for each of the cell lines, including a decrease in glycolytic flux, decreased net lactate production and an increase in reductive carboxylation of glutamine. Reductive carboxylation has previously been observed to increase under hypoxia; but lactate’s effect on reductive carboxylation has not been previously reported. The implications of these findings towards understanding cancer metabolism flexibility and its impact on the tumor microenvironment will be discussed.
Daniel Odenwelder, Sarah Harcum, and Arthur Brodksy, "Investigating the reverse Warburg effect: How high extracellular lactate alters breast cancer metabolism" in "Cell Culture Engineering XV", Robert Kiss, Genentech Sarah Harcum, Clemson University Jeff Chalmers, Ohio State University Eds, ECI Symposium Series, (2016). http://dc.engconfintl.org/cellculture_xv/118