2. Academic Validation
  3. Mitochondrial TXNRD3 confers drug resistance via redox-mediated mechanism and is a potential therapeutic target in vivo

Mitochondrial TXNRD3 confers drug resistance via redox-mediated mechanism and is a potential therapeutic target in vivo

  • Redox Biol. 2020 Sep;36:101652. doi: 10.1016/j.redox.2020.101652.
Xiaoxia Liu 1,  Yanyu Zhang 2,  Wenhua Lu 2,  Yi Han 2,  Jing Yang 2,  Weiye Jiang 2,  Xin You 2,  Yao Luo 2,  Shijun Wen 2,  Yumin Hu 2,  Peng Huang 3
Affiliations

Affiliations

  • 1 Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China; The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Supported By National Key Clinical Discipline, Guangzhou, 510655, China.
  • 2 Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.
  • 3 Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China; Metabolic Innovation Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China. Electronic address: huangpeng@sysucc.org.cn.
PMID: 32750669 DOI: 10.1016/j.redox.2020.101652
Abstract

Alterations in ROS metabolism and redox signaling are often observed in Cancer cells and play a significant role in tumor development and drug resistance. However, the mechanisms by which redox alterations impact cellular sensitivity to Anticancer drugs remain elusive. Here we have identified the mitochondrial isoform of thioredoxin reductase 3 (mtTXNRD3), through RT-PCR microarray screen, as a key molecule that confers drug resistance to sorafenib and Other clinical Anticancer agents. High expression of mtTXNRD3 is detected in drug-resistant leukemia and hepatocellular carcinoma cells associated with significant metabolic alterations manifested by low mitochondrial respiration and high glycolysis. Mechanistically, high mtTXNRD3 activity keeps the mitochondrial thioredoxin2 (Trx2) in a reduced stage that in turn stabilizes several key survival molecules including HK2, Bcl-xL, Bcl-2, and Mcl-1, leading to increased cell survival and drug resistance. Pharmacological inhibition of thioredoxin reductase by auranofin effectively overcomes such drug resistance in vitro and in vivo, suggesting that targeting this redox mechanism may be a feasible strategy to treat drug-resistant Cancer.

Keywords

Auranofin; Drug resistance; Mitochondria; Redox modulation; Sorafenib; TXNRD3.

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