Objective To investigate tumor-selective replicating adenovirus ZD55-interleukin (IL)-24 induces B-cell lymphoma/leukemia-2 (bcl-2) S-nitrosylation decline and further facilitates bcl-2 ubiquitin degradation,leading to melanoma cell apoptosis.Methods ZD55-IL-24 was transfected into melanoma A375 cells,bcl-2 S-nitrosylation,bcl-2 ubiquitination,bcl-2 protein level and downstream Caspase protein were detected by Western blotting and Co-IP.Furthermore,nitric oxide (NO) regulator single nucleotide polymorphism (SNP),PTIO and DTT were used to coffirm the relationship between bcl-2 S-nitrosylation and its ubiquitination.Results ZD55-IL-24 induced the bcl-2 protein level decline in time-dependent manner.Moreover,ZD55-IL-24 decreased bcl-2 S-nitrosylation and increased bcl-2 ubiquitination,which initiated the Caspase signal pathway activation and promoted melanoma cell apoptosis from 11％ to 72％ ; NO donor SNP promoted bcl-2 S-nitrosylation but restrained bcl-2 ubiquitination,which restored bcl-2 protein level.Moreover,melanoma cell apoptosis decreased from 68％ to 19％.In contrast,SNP antagonist DTT reversed the above results by enhancing cell apoptosis to 93 ％.NO inhibitor PTIO similarly increased melanoma cell apoptosis to 85％.Conclusion ZD55-IL-24 reduced bcl-2 S-nitrosylation and facilitated bcl-2 ubiquitin proteasome degradation,thereby resulting in melanoma cell apoptosis.