Erratum (Retracted article): Role of p53 and p38 MAP kinase in nitric oxide-induced G2/M arrest and apoptosis in the human lung carcinoma cells (Carcinogenesis (2003) 10.1093/carcin/bgg155)

In this report, we investigated the role of nitric oxide (NO) in regulating cell cycle arrest and apoptosis in the human lung carcinoma cells. Cadmium (Cd) is a well-known environmental toxicant and human carcinogen. CdCl₂ (80 μM, 2 h) increased the inducible nitric oxide synthase (iNOS) proteins and enhanced the NO production in CL3 human lung adenocarcinoma cells. The cytotoxicity, caspase-3 activation, and apoptosis induced by Cd were reduced when iNOS activity was inhibited by N^G-nitro-L-arginine methyl ester (L-NAME) or when NO was scavenged by 2-(4-carboxyphenyl -4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (cPTIO). Exposure to exogenous NO, derived from 400 μM S-nitroso-N-acetyl-penicillamine (SNAP), for 24 h also induced the cytotoxicity, caspase-3 activation and apoptosis in CL3 cells, which were inhibited by cPTIO but not by L-NAME. Thus Cd and SNAP induced apoptosis via iNOS-dependent and iNOS-independent pathway, respectively. In addition, SNAP inhibited cell growth and induced G₂/M arrest in CL3 cells. Total p53 and phospho-p53 (Ser-15) proteins were increased by SNAP in a concentration-dependent manner. H1299-tsp53 cells that expressed functional p53^Leu173 (at 32°C) were much more effective in the induction of p21 and more resistant to cytotoxicity than those expressed mutant p53^Leu173 (at 37°C) when treated with SNAP. In contrast, cells with mutant p53^Leu173 increased Cd- and SNAP-induced activation of caspase-3 and p38 mitogen-activated protein (MAP) kinase. Moreover, Cd- and SNAP-induced caspase-3 activation and cell death were reduced when CL3 cells expressed a dominant negative p38 protein. These findings suggest that p53 elevates the p21 level, which mediates NO-induced G₂/M arrest and reduces cell death. In contrast, p38 MAP kinase plays a major role in the NO-induced apoptosis via the caspase-3 activation in a p53 independent pathway.