Hydrogen sulfide-induces DNA damage and changes in apoptotic gene expression in human lung fibroblast cells.
Hydrogen sulfide (H2S) has been shown previously to exert proapoptotic activity. However, the mechanism(s) by which H2S affects cell growth and function have not been addressed adequately. In this study, cultured human lung fibroblasts were treated with the H2S donor NaHS (10-75 microM; 12-48 h). NaHS caused a concentration-dependent increase in micronuclei formation (indicating DNA damage) and cell cycle arrest (G1 phase). NaHS increased expression of ku 70 and ku 80 but did not affect the expression of other DNA repair proteins such as proliferating cell nuclear antigen (PCNA) or replication protein A (rNase protection assay). NaHS treatment also resulted in stabilization of p53 coupled with induction of downstream proteins such as p21, Bax, and cytochrome c, as well as translocation of Bax from the cytosol to the mitochondria and release of cytochrome c from mitochondria. NaHS did not up-regulate cell levels of the antiapoptotic protein, Bcl-2. We propose that the genotoxic action of H2S propels the cell toward apoptotic death triggered initially by stabilization of p53 and subsequently involving a cascade of downstream products. These results are of significance as they uncover a hitherto unknown and very fundamental role for H2S in determining cell fate.
Baskar
Rajamanickam
R
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 18 Medical Dr., Singapore 117597.
Li
Ling
L
Moore
Philip Keith
PK
D017209:Apoptosis / Q000235:genetics*; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D004249:DNA Damage; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015162:Micronucleus Tests; D005810:Multigene Family; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D006862:Hydrogen Sulfide