Involvement of Ras in survival responsiveness to nitric oxide toxicity in pheochromocytoma cells.

摘要: Nitric oxide (NO) plays a key role in attenuation of tumor growth by activated macrophages that generate large amount cytotoxic/cytostatic free radicals. However, some cells may survive from NO cytotoxicity and continue to proliferate malignant tumors. Since protooncogene product Ras was shown be NO, this study investigated the involvement cell survival response pheochromocytoma (PC12) cells. Treatment with inhibitor or constitutive expression dominant negative markedly increased NO-induced death. NO-resistant PC12 (PC12-NO-R) exhibited higher steady state activity than parental Inducible using tetracycline-on (Tet-on) system mutants (dominant active Ras) demonstrated blockade death whereas enhancement attenuated Furthermore, inducible NO-insensitive mutant selectively cellular vulnerability but not ROS. extracellular signal-regulated kinase (Erk) blocker synergistically These observations suggest critical factor for toxicity pharmacological agents affecting enhance efficacy NO-mediated therapies.