Inhibition of hydrogen sulfide biosynthesis sensitizes lung adenocarcinoma to chemotherapeutic drugs by inhibiting mitochondrial DNA repair and suppressing cellular bioenergetics.
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.
Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas 77555, USA.
Bartosz
B
Szczesny
Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas 77555, USA.
Michela
M
Marcatti
Department of Surgery, University of Texas Medical Branch, Galveston, Texas 77555, USA.
John R
JR
Zatarain
Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas 77555, USA.
Nadiya
N
Druzhyna
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77555, USA.
John E
JE
Wiktorowicz
Department of Molecular Immunology and Toxicology, National Institute of Oncology, Budapest 1122, Hungary.
Péter
P
Nagy
Department of Surgery, University of Texas Medical Branch, Galveston, Texas 77555, USA.
Mark R
MR
Hellmich
Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas 77555, USA.
Csaba
C
Szabo
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004260:DNA Repair / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000235:genetics; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects; D006862:Hydrogen Sulfide / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004272:DNA, Mitochondrial; D006862:Hydrogen Sulfide