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Research Research teams Redox Biology Research Group Current grant-funded projects

Current grant-funded projects

Project 1, Supported by the Hungarian ELKH Foundation.  “Sulfur Metabolism Under Stress”

Nicotinamide adenine dinucleotide phosphate (NADPH) is the source of electrons for most biological reduction reactions, including most disulfide reductions; yet only two enzymes are known that can use NADPH to reduce a disulfide bond: thioredoxin reductase (TrxR) and GSH-disulfide (GSSG)-reductase (Gsr). Classical studies showed that in model organisms across phyla, elimination of both TrxR and Gsr is lethal. Nonetheless, in 2015 Prof. E.E. Schmidt from the RBL directed the team that showed that mice in which the liver lacked both TrxR1 and Gsr (“TrxR1/Gsr-null”) were viable1.  Survival was dependent on the activity of a pathway that consumed the essential sulfur amino acid methionine and had not previously been thought to contribute significantly to cellular disulfide reducing power1.  Interestingly, this pathway does not use NADPH in the cells where it acts but, rather, scavenges reducing power by scavenging the reduced sulfur out of dietary methionine.  As such, this represented the first known disulfide reduction pathway reported that was shown to be independent of an upstream intracellular NADPH-dependent disulfide reduction (1,2,3).  The Nagy team demonstrated that sulfur metabolic pathways play major roles in cellular protection against oxidative stress via a) converting protein Cys residues to the corresponding persulfide derivatives (4,5,6) or b) by interactions of Reactive Sulfur Species with metalloproteins (7,8,9) This project investigates the mechanisms by which sulfur metabolism can be re-wired in cells lacking enzymes of the NADPH reducing machinery to protect them against oxidative stress. This project investigates the mechanisms by which sulfur metabolism can be re-wired to protect against oxidative stress.

 

Project 2, Supported by a Hungarian K-22 award. “Understanding and targeting redox systems in a preclinical liver cancer model”

Liver cancer the 3rd most deadly cancer worldwide; 9th most deadly in Hungary. Metabolic and anabolic activities of cancer cells cause increased oxidant production. Tumors are also exposed to inflammatory responses, hypoxia, and therapeutic interventions that each further increase oxidative stress. In combination, this has been predicted to make cancer cells more susceptible to disruption of endogenous antioxidant systems than are non-transformed cells yet, to date, attempts to target cancer redox susceptibilities in animal models or clinical trials have not found much success. We hypothesize that targeting the major redox systems activates the noncanonical backup systems that we have discovered, and perhaps others (10). We here are investigating these mouse preclinical liver cancer models. We expect that this project will uncover systems that provide oxidant resistance in liver cancers, which in turn could lead to development of new therapeutic strategies.

References:

  1. Eriksson, S.;Prigge, J. R.;  Talago, E. A.;  Arner, E. S.; Schmidt, E. E., Dietary methionine can sustain cytosolic redox homeostasis in the mouse liver. Nature communications 2015, 6, 6479.
  2. Miller, C. G.;Holmgren, A.;  Arner, E. S. J.; Schmidt, E. E., NADPH-dependent and -independent disulfide reductase systems. Free Radic Biol Med 2018, 127, 248-261.
  3. Miller, C. G.; Schmidt, E. E., Disulfide reductase systems in liver. Br J Pharmacol 2019, 176 (4), 532-543.
  4. Nagy P, Dóka É, Ida T, Akaike T. Measuring Reactive Sulfur Species and Thiol Oxidation States: Challenges and Cautions in Relation to Alkylation-Based Protocols.
    Antioxid Redox Signal. 2020 Dec 1;33(16):1174-1189. doi: 10.1089/ars.2020.8077. Epub 2020 Jul 30. PMID: 32631072
  5. Erdélyi K, Ditrói T, Johansson HJ, Czikora Á, Balog N, Silwal-Pandit L, Ida T, Olasz J, Hajdú D, Mátrai Z, Csuka O, Uchida K, Tóvári J, Engebraten O, Akaike T, Børresen Dale AL, Kásler M, Lehtiö J, Nagy P. Reprogrammed transsulfuration promotes basal-like breast tumor progression via realigning cellular cysteine persulfidation.
    Proc Natl Acad Sci U S A. 2021 Nov 9;118(45):e2100050118. doi: 10.1073/pnas.2100050118. PMID: 34737229
  6. Czikora Á, Erdélyi K, Ditrói T, Szántó N, Jurányi EP, Szanyi S, Tóvári J, Strausz T, Nagy P. Cystathionine β-synthase overexpression drives metastatic dissemination in pancreatic ductal adenocarcinoma via inducing epithelial-to-mesenchymal transformation of cancer cells.
    Redox Biol. 2022 Oct 10;57:102505. doi: 0.1016/j.redox.2022.102505.
    PMID: 36279629
  7. Péter Nagy Mechanistic chemical perspective of hydrogen sulfide signaling Methods Enzymol. 2015; 554:3-29. doi: 10.1016/bs.mie.2014.11.036.
  8. Zoltán Pálinkás, Paul G Furtmüller, Attila Nagy, Christa Jakopitsch, Katharina F Pirker, Marcin Magierowski, Katarzyna Jasnos, John L Wallace, Christian Obinger, Péter Nagy Interactions of hydrogen sulfide with myeloperoxidase Br J Pharmacol. 2015 Mar;172(6):1516-32. doi: 10.1111/bph.12769.
  9. Garai D, Ríos-González BB, Furtmüller PG, Fukuto JM, Xian M, López-Garriga J, Obinger C, Nagy P. Mechanisms of myeloperoxidase catalyzed oxidation of H2S by H2O2 or O2 to produce potent protein Cys-polysulfide-inducing species. Free Radic Biol Med. 2017 Dec;113:551-563. doi: 10.1016/j.freeradbiomed.2017.10.384.
  10. Miller, C. G.; Schmidt, E. E., Sulfur Metabolism Under Stress. Antioxid Redox Signal 2020, 33 (16), 1158-1173.