PEPCK in cancer cell starvation

Nutrient and oxygen (O2) deprivation are frequent in solid cancers. Angiogenesis is activated early in cancer growth, however, the newly formed vascular network is aberrant and shows irregular blood flow [1]. Moreover, cancer cells themselves contribute to gradients for nutrients like glucose due to high consumption. The concentration of glucose was estimated to be on average 3 to 10 times lower in tumors compared to corresponding normal tissues [2]. Using imaging bioluminescence, glucose levels were shown to be even close to zero in the viable rim around necroses [3]. Cancer cells therefore must adapt to the varying concentration of nutrients, especially glucose. Low availability of glucose dramatically reduces metabolic flux via glycolysis. Accordingly, cancer cells facing chronic glucose limitation were found to increasingly rely on mitochondrial oxidative phosphorylation for sustained proliferation [2]. Besides energy shortage, a reduction of the glycolytic flux potentially results in a drop in cellular intermediates needed for the synthesis of crucial building blocks, like ribose or glycerol - unless these intermediates are generated by alternative metabolic pathways.