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

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.

SUBMITTER: Liu X

PROVIDER: S-EPMC7397405 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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

Liu Xiaoxia X Zhang Yanyu Y Lu Wenhua W Han Yi Y Yang Jing J Jiang Weiye W You Xin X Luo Yao Y Wen Shijun S Hu Yumin Y Huang Peng P

Redox biology 20200723

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 expr ...[more]

PMID: 32750669

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Project description:Bloodstream forms of four populations of the livestock pathogen Trypanosoma congolense, isolated from different natural infections, have been shown to exhibit a wide range of sensitivities to the trypanocide isometamidium chloride (Samorin(R)). In mice the 50% curative doses (CD50) for Samorin range from 0.007 to 20 mg/kg body weight. Uptake of isometamidium chloride demonstrated Michaelis-Menten-type kinetics in all the populations, with Km values in the range 0.35-0.87 microM, and Vmax varied from 17 to 216 pmol/min per 10(8) cells. The magnitude of Vmax was correlated with sensitivity to the drug. In contrast, no correlation was observed between Km values and drug sensitivity. Pulse-chase experiments indicated two compartments for accumulation of drug. The first consists of freely diffusible drug that is invariant between populations; the other consists of retained isometamidium, which is of variable magnitude between the populations and is correlated with drug sensitivity. Autoradiography and fluorescence microscopy demonstrated initial, rapid accumulation of the drug within the mitochondrion, specifically the kinetoplast. In a drug-sensitive population of T. congolense, agents affecting mitochondrial function were shown to produce dose-dependent inhibition of mitochondrial membrane potential (DeltaPsimito), as measured by the accumulation of the lipophilic cations [3H]methyltriphenylphosphonium iodide or rhodamine 123. The agents also produced parallel inhibition of isometamidium uptake, suggesting an involvement of DeltaPsimito in the accumulation of the drug. When characterized in each of the four populations, the spontaneous DeltaPsimito was shown to be characteristic of each population and was correlated with Vmax for drug uptake and sensitivity to the drug in vitro and in vivo. We therefore conclude that in T. congolense DeltaPsimito is an important determinant of the rate and accumulation of the trypanocide isometamidium chloride. Populations of this trypanosome species vary with respect to DeltaPsimito, which is correlated with sensitivity to isometamidium. We suggest that when exposed to drug, the selection of such populations represents a novel mechanism of drug resistance in protozoan parasites.

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

Publications

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

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