Inhibitor titrations reveal low control of glyceraldehyde 3-phosphate dehydrogenase and high control of hexokinase on glycolytic flux in an aggressive triple-negative breast cancer cell line

Abstract

The glycolytic flux, and in particular lactate production, is strongly increased in cancer cells compared to normal cells, a characteristic often referred to as aerobic glycolysis or the Warburg effect. This makes the glycolytic pathway a potential drug target, in particular if the flux control distribution in the pathway has shifted due to the metabolic reprogramming in cancer cells. The flux response of a drug is dependent on both the sensitivity of the target to the drug and the flux control of the target, and both these characteristics can be exploited to obtain selectivity for cancer cells. Traditionally drug development programs have focused on selective sensitivity of the drug, not necessarily focussing on the flux control of the target. We determined the flux control of two steps that have been suggested to have high control in cancer cells, using two inhibitors, iodoacetic acid and 3-bromopyruvate, and measured a flux control of the glyceraldehyde 3-phosphate dehydrogenase close to zero, while the hexokinase holds 50% of all flux control in glycolysis in an invasive cancer cell line MDA-mb-231.

Keywords: Breast cancer; GAPDH; Glycolysis; HK; Metabolic control analysis; Warburg effect.