Cu,Zn-superoxide dismutase-dependent apoptosis induced by nitric oxide in neuronal cells

Maria Rosa Ciriolo, Angelo De Martino, Emanuela Lafavia, Luisa Rossi, Maria Teresa Carrì, Giuseppe Rotilio

Research output: Contribution to journalArticlepeer-review

Abstract

Nitric oxide (NO) challenge to human neuroblastoma cells (SH-SY5Y) ultimately results in apoptosis. Tumor suppressor protein p53 and cell cycle inhibitor p21 accumulate as an early sign of S-nitrosoglutathione-mediated toxicity. Cytochrome c release from mitochondria and caspase 3 activation also occurred. Cells transfected with either wild type (WT) or mutant (G93A) Cu,Zn-superoxide dismutase (Cu,Zn-SOD) produced comparable amounts of nitrite/nitrate but showed different degree of apoptosis. G93A cells were the most affected and WT cells the most protected; however, Cu,Zn-SOD content of these two cell lines was 2-fold the SH-SY5Y cells under both resting and treated conditions. We linked decreased susceptibility of the WT cells to higher and more stable Bcl-2 and decreased reactive oxygen species. Conversely, we linked G93A susceptibility to increased reactive oxygen species production since simultaneous administration of S-nitrosoglutathione and copper chelators protects from apoptosis. Furthermore, G93A cells showed a significant decrease of Bcl-2 expression and, as target of NO-derived radicals, showed lower cytochrome c oxidase activity. These results demonstrate that resistance to NO-mediated apoptosis is strictly related to the level and integrity of Cu,Zn-SOD and that the balance between reactive nitrogen and reactive oxygen species regulates neuroblastoma apoptosis.

Original languageEnglish
Pages (from-to)5065-5072
Number of pages8
JournalJournal of Biological Chemistry
Volume275
Issue number7
DOIs
Publication statusPublished - Feb 18 2000

ASJC Scopus subject areas

  • Biochemistry

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