Exploiting the pentose phosphate pathway as therapeutic target in hepatocellulcar carcinoma treatment

Abstract

Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is the fifth most prevalent and the third most lethal cancer worldwide. Only a minority of HCC patients are suitable for surgical treatments. HCC has a high recurrent rate and is resistant to conventional chemotherapies. So far, there is only one FDA-approved targeted therapy, Sorafenib, for advanced HCC patients. Knowledge regarding the metabolic regulation in HCC is warranted for the identification of novel therapeutic targets. HCC cells experience an elevation of oxidative stress due to aberrant signaling pathways and activated metabolic machinery. To combat oxidative stress, we found that HCC cells had increased reliance on the pentose phosphate pathway (PPP), a major antioxidant producing pathway. PPP is composed of the oxidative and the non-oxidative arms. We showed that all enzymes in the PPP were over-expressed in human HCC. Transketolase (TKT), a reversible enzyme in the non-oxidative arm which controls the direction of the metabolic flux in the PPP, was the most upregulated enzyme and its expression was governed by the NRF2/KEAP1/BACH1 oxidative stress sensor pathway in HCC. Metabolomic and metabolic flux analyses suggested that knockdown of TKT truncated the PPP, forcing metabolites to enter the oxidative arm. This led to an accumulation of ribulose-5-phosphate (Ru5P) and ribose-5-phosphate (R5P) which in turn inhibited the activity of glucose-6-phosphate dehydrogenase (G6PD), the NADPH-producing enzyme in the PPP. As a result, knockdown of TKT drastically increased reactive oxygen species (ROS) accumulation and caused ROS-associated cell cycle delay. Knockdown of TKT markedly reduced NADPH production and repressed HCC growth in vitro and in vivo. Therapeutically, disturbing the redox homeostasis of HCC cells by stable knockdown or pharmacologic inhibition of TKT sensitized cancer cells to Sorafenib treatment in vitro and in vivo. Here, using HCC as a cancer model, we highlighted the pro-tumorigenic roles of antioxidants. We also demonstrated that the PPP can be exploited as a therapeutic target for cancer treatment.