Judit Bátor, Judit Varga, József Szeberényi
Department of Medical Biology and Central Electron Microscopic Laboratory, University of Pécs, Medical School, Pécs, Hungary
Nitric oxide is a mediator of a diverse array of inter- and intracellular signal transduction processes. Nitric oxide exerts its effects via multiple mechanisms: covalently modifies various target proteins (nitrosylation) thereby changing their activity, binds to heavy metal ions that are components of protein complexes, and activates the cGMP pathway. Higher concentrations of nitric oxide cause cellular stress called nitrosative stress. It can lead to apoptotic or necrotic cell death.
Sodium nitroprusside as a nitric oxide donor was used in our studies to analyze signaling events of nitrosative stress. Cytotoxic concentrations of sodium nitroprusside activated several pro-apoptotic mechanisms (stimulated stress kinase pathways mediated by JNK and p38MAPK, inhibited the translation initiation factor eIF2α, leaded to phosphorylation and stabilization of p53 protein and activation of caspases). It inhibited Akt-mediated antiapoptotic signaling and expression of Bcl2 protein. Simultaneously, stimulation of the pro-survival ERK pathway was also observed, providing a certain degree of protection. Surprisingly, pretreatment with a lower dose of the nitric oxide donor effectively protected the cells from the toxic effect of the higher dose treatment.
It can be thus concluded that nitric oxide modulates various signaling pathways. The fate of the cell is determined by the collective impact of these pathways on the cell survival.