Abstract 2453: Transketolase (TKT) is a critical component of the metabolic machinery of hepatocellular carcinoma (HCC)

Abstract

Abstract Hepatocellular carcinoma, HCC, is one of the commonest malignant cancers in human liver. The prognosis of HCC patients is extremely poor mainly because of late symptom presentation and absence of effective therapy. Liver is the metabolic engine that maintains the homeostasis of various nutrients; nevertheless, how the metabolic reprogramming of HCC cells benefits tumor progression remains largely unknown. Understanding the metabolic machinery of HCC is important for the development of new therapeutic approaches for HCC. Increased glucose intermediates through glycolysis and the pentose phosphate pathway (PPP) is a metabolic signature of cancer. The PPP works collaboratively with glycolysis to support rapid tumor growth by producing NADPH, the major antioxidant in the cells, and ribose-5-phosphate, the backbone of RNA. One of the key enzymes that connect PPP with glycolysis is the transketolase family (TK). The TK family comprises 3 members namely transketolase (TKT), TKT-like 1 (TKTL1) and TKTL2. Many studies have indicated that strong TKTL1 protein expression was correlated with invasive features and poor clinical outcome in other cancers. However, our transcriptome sequencing data from 16 pairs of human HCC and non-tumorous liver (NT) tissues revealed that (1) the TKT is the predominant TK member in the liver and HCC; (2) TKT, but not other TK family members, is overexpressed in HCC. In an expanded HCC cohort consisting of 60 human HCC cases, we confirmed that TKT is significantly overexpressed and is closely associated with aggressive HCC clinicopathological features including tumor microsatellite formation (P = 0.04), venous invasion (P = 0.01), and large tumor size (P = 0.04). Stable knockdown of TKT by various short hairpin RNA (shRNA) sequences in multiple HCC cell lines (MHCC97L, SMMC-7721, and BEL-7402) consistently suppressed cell growth, elevated intracellular ROS level (CM-H2DCFDA staining), and decreased glucose uptake (2-NBDG staining). In line with the in vitro observations, stable knockdown of TKT drastically impeded HCC growth in orthotropic and subcutaneous tumor models. More interestingly, pharmacological inhibition and genetic knockdown of TKT by oxythiamine (OT) and shRNA, respectively, sensitized HCC cells to the treatment of 2-deoxyglucose (2-DG), a glycolysis inhibitor. Inhibition of PPP and glycolysis by co-treatment of OT and 2-DG completely suppressed HCC growth. Taken together, our present data suggested that TKT overexpression strongly favors HCC cell growth in vitro and in vivo. Our data also showed that TKT is a critical component of the metabolic machinery of HCC and therefore an attractive therapeutic target. Citation Format: Mingjing Xu, Carmen Chak-Lui Wong, Irene Oi-Lin Ng. Transketolase (TKT) is a critical component of the metabolic machinery of hepatocellular carcinoma (HCC). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2453. doi:10.1158/1538-7445.AM2014-2453