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.
Highlights
Survival - all important factors in cancer biology[16,17,18,19,20,21,22]
Increased expression of the various H2S-generating enzymes, and increased H2S production was noted in multiple cultured lung adenocarcinoma cell lines (A549, H522 and H1944), while lung epithelial cells derived from non-malignant tissue (BEAS 2B) showed significantly lower levels of H2S production (Figs 1C,D and S1B)
As expected from the roles of cystathionine beta-synthase (CBS) and cystathionine gamma lyase (CSE) in the transsulfuration pathway, aminooxyacetic acid (AOAA) induced the accumulation of serine and homocysteine and decreased cystathionine levels in AOAA-treated A549 cells (Fig. S1C)
Summary
Lung adenocarcinoma tumors and cultured cells express high level of H2S-producing enzymes. The interaction between EXOG with APE1, PolG or Lig[3], but not between nuclear-specific DNA repair enzymes FEN1 and PolB, was markedly reduced by H2S biosynthesis inhibition in lung adenocarcinoma (but not in normal epithelial cells) (Fig. 2L). No changes in bioenergetics parameters were detected in A549 cells treated with various concentration of serine and homocysteine (Fig. S3D) From these data, we conclude that lung adenocarcinoma cells are protected from mtDNA damaging agents (e.g., ROS) through the H2S-dependent enhancement of mtDNA repair mechanisms, resulting in cancer cell-specific improvements in mitochondrial electron transport and cellular ATP generation. Comprehensive diagnostic blood profile analysis showed no signs of organ injury in mice treated with the AOAA/irinotecan combination (Table S1)
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