Glutathione-related systems and modulation of extracellular signal-regulated kinases are involved in the resistance of AGS adenocarcinoma gastric cells to diallyl disulfide-induced apoptosis.
We have previously characterized the cytotoxic action of diallyl disulfide (DADS) on neuroblastoma cells, and we have shown the crucial role of an early and massive reactive oxygen species production in the induction of c-Jun NH(2)-terminal kinase-mediated apoptotic pathway. In the present work, we report that DADS is ineffective in inducing apoptosis in a human adenocarcinoma gastric cell line (AGS). In particular, we show that AGS cells are able to recover from the p53/p21-mediated cell cycle arrest in the G(2)-M phase upon DADS treatment without committing cells to death. This event is most likely due to a peculiar surviving pathway of these cells involving: (a) the formation of mixed disulfides between reduced glutathione (GSH) and protein thiols, (b) a higher and inducible glutathione peroxidase activity, and/or (c) an efficient modulation of the phospho-active levels of the extracellular signal-regulated kinases 1 and 2 (ERK 1/2). Moreover, by increasing glutathione peroxidase expression or GSH concentrations, cell cycle arrest is fully abolished; the apoptotic death is induced by either decreasing the availability of intracellular GSH or inhibiting the reactivation of ERK 1/2. Altogether, our data show that ERK 1/2 participates in the active proliferation of AGS cells and that an efficient reactive oxygen species buffering system makes these cells resistant to DADS-mediated detrimental effects.
Filomeni
Giuseppe
G
Department of Biology, University of Rome Tor Vergata, Italy.
Aquilano
Katia
K
Rotilio
Giuseppe
G
Ciriolo
Maria R
MR
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000498:Allyl Compounds / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004220:Disulfides / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D016195:G2 Phase / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000378:metabolism; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013438:Sulfhydryl Compounds / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000498:Allyl Compounds; D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004220:Disulfides; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; D016159:Tumor Suppressor Protein p53; C028009:diallyl disulfide; D005979:Glutathione Peroxidase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D005978:Glutathione