Exploring glycolytic adaptations in cancer cells

Altered glycolytic metabolism is well-documented as a hallmark of cancer. Indeed, it is established that compared to normal cells, cancer cells prefer using glycolysis even in normoxic conditions. Even though the Warburg effect was described for the first time in the 1920s, the molecular mechanisms involved are poorly understood. The adaptative stress response to hypoxia and nutrient depletion, as well as several oncogenic drivers, seems to contribute to increased expression of glycolytic enzymes and negative regulation of the tricarboxylic acid cycle and oxidative phosphorylation. The high levels of glycolytic intermediates are essential to sustain the biosynthetic requirements of high-proliferating tumor cells. The lactate-induced acidic microenvironment and the nonglycolytic functions of various glycolytic enzymes also contribute to Warburg effect-induced tumor progression. These roles prompted the development of anticancer therapeutic options targeting the glycolytic pathway. In fact, 57 glycolytic inhibitors were already developed, but most of them still miss preclinical and/or clinical validation.