Understanding the Contribution of the Non-oxidative Pentose Phosphate Pathway to Cancer Cell Metabolism

Abstract

Upregulation of the pentose phosphate pathway is heavily implicated in cancer cell growth and survival due to its involvement in the generation of NADPH for oxidative stress management and ribose-5-phosphate for nucleotide production. In this thesis, I use knockouts of the enzymes of the non-oxidative pentose phosphate pathway in order to investigate perturbations in the metabolisms of cancer cells. I found that ΔRPE, ΔTKT, and ΔPGD knockouts grow significantly slower than wildtype HCT-116 cancer cells, both in vitro and in vivo. I also discovered that enzymes of the non-oxidative pentose phosphate pathway control flux through the oxidative pentose phosphate pathway, and that the oxidative pentose phosphate pathway already overwhelms cellular requirements for ribose-5-phosphate. Rather than net producing ribose-5-phosphate from glycolytic intermediates by running the non-oxidative pentose phosphate pathway backwards, cancer cells utilize the non-oxidative pentose phosphate to shunt accumulating pentose-related metabolites into glycolysis. These results have important implications for future metabolism-based cancer therapies. Simultaneously targeting specific enzymes of the pentose phosphate pathway in tumors may increase the efficacy of traditional pharmaceutical interventions.