Abstract 2445: Oxidative stress induction through TXNRD1 inhibition as a therapeutic strategy in hepatocellular carcinoma treatment
Authors: Lee Derek , Xu Iris Ming Jing , Chiu David Kung Chun , Lai Robin Kit Ho , Wong Chun Ming , Ng Irene Oi Lin , Wong Carmen Chak Lui 
Published: August 2018

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer. It ranks third amongst cancer-related deaths worldwide owing to its late symptom presentation and lack of effective treatment regimens. Compared to normal cells, cancer cells experience distinctly higher amount of oxidative stress from increased reactive oxygen species (ROS) generation contributed by metabolic alterations, or its hypoxic microenvironment. Cancer cells also have a greater capacity of antioxidant production to maintain redox homeostasis. Immense generation of NADPH, a major metabolite and antioxidant is found in cancer cells to combat ROS as confirmed in our previous studies as we identified the folate cycle and pentose phosphate pathway (PPP) as major metabolic pathways responsible for NADPH production in human HCC. NADPH is an electron donor which can reduce and activate different antioxidant systems. The thioredoxin system is a ubiquitously-expressed mammalian antioxidant system activated by NADPH. The transmission of an electron from NADPH to TXN, the ROS-scavenging member of the thioredoxin system, is modulated by thioredoxin reductase 1 (TXNRD1). TXRND1 is the sole activating-enzyme of the thioredoxin system, playing a vital role in maintaining intracellular redox homeostasis. Furthermore, TXNRD1 was found to be significantly over-expressed in human HCC correlated with poor clinical prognosis and patient survival. Genetic inhibition of TXNRD1 via shRNA-knockdown significantly induced oxidative stress which suppressed HCC cell proliferation in vitro and liver tumor formation orthotopically implanted in vivo. Interestingly, TXNRD1-inhibition-induced oxidative stress rendered HCC cells more sensitive towards Sorafenib, its conventional therapeutic agent. This was highlighted by a dramatic induction of ROS-induced apoptosis in vitro and suppression tumor growth in vivo. NRF2, a transcription factor and master regulator against oxidative stress, was confirmed to bind with TXNRD1 using ChIP assay. Both genetic inhibition and pharmacological activation of NRF2 in HCC cells confirmed the dependent relationship between NRF2 and TXNRD1. Therapeutically, pharmacological inhibition of the thioredoxin system using the TXNRD1 inhibitor auranofin greatly sensitized HCC cells towards sorafenib. The synergism was observed through significant induction of ROS resulting in significant cell death in vitro and suppression of tumor formation in vivo. Our investigation demonstrated the induction of oxidative stress, as a result of thioredoxin system inhibition, rendered HCC cells more sensitive towards therapeutic treatment. Contrasting the widely-known, tumorigenic role of ROS, we now shed light on a paradigm-shifting strategy which ROS may be used as a therapeutic adjuvant to combat cancer.

Citation Format: Derek Lee, Iris Ming Jing Xu, David Kung Chun Chiu, Robin Kit Ho Lai, Chun Ming Wong, Irene Oi Lin Ng, Carmen Chak Lui Wong. Oxidative stress induction through TXNRD1 inhibition as a therapeutic strategy in hepatocellular carcinoma treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2445.