Abstract
Transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) plays a crucial role in regulating the expression of genes participating in cellular defense mechanisms against oxidative or xenobiotic insults. However, there is increasing evidence showing that hyperactivation of NRF2 is associated with chemoresistance in several cancers, including hepatocellular carcinoma (HCC), thus making NRF2 an attractive target for cancer therapy. Another important issue in cancer medication is the adverse effects of these substances on normal cells. Here, we attempted to identify a dual-selective NRF2 regulator that exerts opposite effects on NRF2-hyperactivated HCC cells and normal keratinocytes. An antioxidant response element driven luciferase reporter assay was established in Huh7 and HaCaT cells as high-throughput screening platforms. Screening of 3,000 crude extracts from the Taiwanese Indigenous Plant Extract Library resulted in the identification of Beilschmiedia tsangii (BT) root extract as a dual-selective NRF2 regulator. Multiple compounds were found to contribute to the dual-selective effects of BT extract on NRF2 signaling in two cell lines. BT extract reduced NRF2 protein level and target gene expression levels in Huh7 cells but increased them in HaCaT cells. Furthermore, notable combinatory cytotoxic effects of BT extract and sorafenib on Huh7 cells were observed. On the contrary, sorafenib-induced inflammatory reactions in HaCaT cells were reduced by BT extract. In conclusion, our results suggest that the combination of a selective NRF2 activator and inhibitor could be a practical strategy for fine-tuning NRF2 activity for better cancer treatment and that plant extracts or partially purified fractions could be a promising source for the discovery of dual-selective NRF2 regulators.
Highlights
Liver cancer occupies the sixth place regarding cancer incidence and the fourth in cancer mortality rate worldwide
NAD(P)H:quinone oxidoreductase-1 (NQO1), is expressed at the highest abundance in Huh7 cells (Figure S2). These results suggest that Huh7 cells could be considered as an Hepatocellular carcinoma (HCC) cell line with persistent nuclear factor erythroid-derived 2-like 2 (NRF2) activation, and they were used as one screening cell model in this study
A selective NRF2 activator would only activate NRF2 signaling in normal cells; it could ameliorate the adverse effects of anticancer drugs without compromising therapeutic effects
Summary
Liver cancer occupies the sixth place regarding cancer incidence and the fourth in cancer mortality rate worldwide (data source: http://gco.iarc.fr/today/home, accessed date 22 November 2020). Hepatocellular carcinoma (HCC), the major subtype of primary liver cancer, accounts for ~80% of cases [1]. Despite great advances in HCC management, the incidence and mortality rate of HCC are still high due to frequent tumor recurrence after treatment. The nuclear factor erythroid-derived 2-like 2 (NRF2)-Kelch-like ECH-associated protein 1 (KEAP1) pathway is a redox- and xenobiotic-sensitive signaling axis that functions to protect cells against oxidative stress and environmental toxicants through the induction of cytoprotective genes. NRF2 participates in the basal activity and coordinates the induction of genes encoding numerous antioxidant and detoxifying enzymes and related proteins such as catalase (CAT), superoxide dismutase (SOD), NAD(P)H:quinone oxidoreductase-1 (NQO1), heme oxygenase-1 (HO1), glutamate cysteine ligase (GCLC), glutathione S-transferase (GST), glutathione peroxidase (GPX), and thioredoxin (TXN) [3,4]
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