NF‐κB‐mediated up‐regulation of Bcl‐XSand Bax contributes to cytochromecrelease in cyanide‐induced apoptosis

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Abstract
Cyanide induces apoptosis through cytochrome c activated caspase cascade in primary cultured cortical neurons. The underlying mechanism for cytochrome c release from mitochondria after cyanide treatment is still unclear. In this study, the roles of endogenous Bcl-2 proteins in cyanide-induced apoptosis were investigated. After cyanide (100–500 µm) treatment for 24 h, two pro-apoptotic Bcl-2 proteins, Bcl-XS and Bax were up-regulated as shown by western blot and RT-PCR analysis. The expression levels of two antiapoptotic Bcl-2 proteins, Bcl-2 and Bcl-XL, remained unchanged after cyanide treatment, whereas the mRNA levels of Bcl-XS and Bax began to increase within 2 h and their protein levels increased 6 h after treatment. NF-κB, a redox-sensitive transcription factor activated after cyanide treatment, is responsible for the up-regulation of Bcl-XS and Bax. SN50, which is a synthetic peptide that blocks translocation of NF-κB from cytosol to nucleus, inhibited the up-regulation of Bcl-XS and Bax. Similar results were obtained using a specific κB decoy DNA. NMDA receptor activation and reactive oxygen species (ROS) generation are upstream events of NF-κB activation, as blockade of these two events by MK801, l-NAME or PBN inhibited cyanide-induced up-regulation of Bcl-XS and Bax. Up-regulation of pro-apoptotic Bcl-XS and Bax contributed to cyanide-induced cytochrome c release, because SN50 and a specific Bax antisense oligodeoxynucleotide significantly reduced release of cytochrome c from mitochondria as shown by western blot analysis. It was concluded that NF-κB-mediated up-regulation of Bcl-XS and Bax is involved in regulating cytochrome c release in cyanide-induced apoptosis.