Induction of Oxidative Stress via Inhibition of Thioredoxin Reductase 1 is an Effective Therapeutic Approach for Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancer worldwide which lacks effective treatment. Cancer cells experience high levels of oxidative stress due to increased generations of reactive oxygen species (ROS). Increased antioxidant‐producing capacity is therefore found in cancer cells to counteract oxidative stress. The thioredoxin system is a ubiquitous mammalian antioxidant system which scavenges ROS and we demonstrate that it is vital for HCC growth as it maintains intracellular reduction‐oxidation (redox) homeostasis. Transcriptome sequencing in human HCC samples revealed significant over‐expression of thioredoxin reductase 1 (TXNRD1), the cytosolic subunit and key enzyme of the thioredoxin system, with significant correlations to poorer clinicopathological features and patient survival. Driven by the transcriptional activation of nuclear factor (erythroid‐derived 2)–like 2 (NRF2), master protector against oxidative stress, TXNRD1 counteracts intracellular ROS produced in human HCC. Inhibition of TXNRD1 via genetic inhibition hindered the proliferation of HCC cells and also induced apoptosis in vitro. Administration of pharmacological TXNRD1 inhibitor, auranofin (AUR), effectively suppressed the growth of HCC tumors induced using the hydrodynamic tail‐vein injection and orthotopic implantation models in vivo. Furthermore, AUR sensitized HCC cells towards the conventional therapeutic Sorafenib.

Conclusion

Our study highlights the reliance of HCC cells on antioxidants for redox homeostasis and growth advantage. Targeting TXNRD1 resulted in dramatic accumulations of ROS which was found to be an effective approach for the suppression of HCC tumor growth.

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