Inhibition of hydrogen sulfide biosynthesis sensitizes lung adenocarcinoma to chemotherapeutic drugs by inhibiting mitochondrial DNA repair and suppressing cellular bioenergetics

Bartosz Szczesny, Michela Marcatti, John R. Zatarain, Nadiya Druzhyna, John E. Wiktorowicz, Péter Nagy, Mark Hellmich, Csaba Szabo

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Abstract

Therapeutic manipulation of the gasotransmitter hydrogen sulfide (H2S) has recently been proposed as a novel targeted anticancer approach. Here we show that human lung adenocarcinoma tissue expresses high levels of hydrogen sulfide (H2S) producing enzymes, namely, cystathionine beta-synthase (CBS), cystathionine gamma lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST), in comparison to adjacent lung tissue. In cultured lung adenocarcinoma but not in normal lung epithelial cells elevated H2S stimulates mitochondrial DNA repair through sulfhydration of EXOG, which, in turn, promotes mitochondrial DNA repair complex assembly, thereby enhancing mitochondrial DNA repair capacity. In addition, inhibition of H2S-producing enzymes suppresses critical bioenergetics parameters in lung adenocarcinoma cells. Together, inhibition of H2S-producing enzymes sensitize lung adenocarcinoma cells to chemotherapeutic agents via induction of mitochondrial dysfunction as shown in in vitro and in vivo models, suggesting a novel mechanism to overcome tumor chemoresistance.

Original languageEnglish (US)
Article number36125
JournalScientific Reports
Volume6
DOIs
StatePublished - Nov 3 2016

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Hydrogen Sulfide
Mitochondrial DNA
DNA Repair
Energy Metabolism
Pharmaceutical Preparations
Gasotransmitters
Enzymes
Cystathionine gamma-Lyase
Cystathionine beta-Synthase
Lung
Epithelial Cells
Adenocarcinoma of lung
Neoplasms
Therapeutics

ASJC Scopus subject areas

  • General

Cite this

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abstract = "Therapeutic manipulation of the gasotransmitter hydrogen sulfide (H2S) has recently been proposed as a novel targeted anticancer approach. Here we show that human lung adenocarcinoma tissue expresses high levels of hydrogen sulfide (H2S) producing enzymes, namely, cystathionine beta-synthase (CBS), cystathionine gamma lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST), in comparison to adjacent lung tissue. In cultured lung adenocarcinoma but not in normal lung epithelial cells elevated H2S stimulates mitochondrial DNA repair through sulfhydration of EXOG, which, in turn, promotes mitochondrial DNA repair complex assembly, thereby enhancing mitochondrial DNA repair capacity. In addition, inhibition of H2S-producing enzymes suppresses critical bioenergetics parameters in lung adenocarcinoma cells. Together, inhibition of H2S-producing enzymes sensitize lung adenocarcinoma cells to chemotherapeutic agents via induction of mitochondrial dysfunction as shown in in vitro and in vivo models, suggesting a novel mechanism to overcome tumor chemoresistance.",
author = "Bartosz Szczesny and Michela Marcatti and Zatarain, {John R.} and Nadiya Druzhyna and Wiktorowicz, {John E.} and P{\'e}ter Nagy and Mark Hellmich and Csaba Szabo",
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AU - Szczesny, Bartosz

AU - Marcatti, Michela

AU - Zatarain, John R.

AU - Druzhyna, Nadiya

AU - Wiktorowicz, John E.

AU - Nagy, Péter

AU - Hellmich, Mark

AU - Szabo, Csaba

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