MDA-7/IL-24 induces Bcl-2 denitrosylation and ubiquitin-degradation involved in cancer cell apoptosis.

Abstract

MDA-7/IL-24 was involved in the specific cancer apoptosis through suppression of Bcl-2 expression, which is a key apoptosis regulatory protein of the mitochondrial death pathway. However, the underlying mechanisms of this regulation are unclear. We report here that tumor-selective replicating adenovirus ZD55-IL-24 leads to Bcl-2 S-denitrosylation and concomitant ubiquitination, which take part in the 26S proteasome degradation. IL-24-siRNA completely blocks Bcl-2 ubiquitination via reversion of Bcl-2 S-denitrosylation and protects it from proteasomal degradation which confirmed the significant role of MDA-7/IL-24 in regulating posttranslational modification of Bcl-2 in cancer cells. Nitric oxide (NO) is a key regulator of protein S-nitrosylation and denitrosylation. The NO donor, sodium nitroprusside (SNP), down-regulates Bcl-2 S-denitrosylation, attenuates Bcl-2 ubiquitination and subsequently counteracts MDA-7/IL-24 induced cancer cell apoptosis, whereas NO inhibitor 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxy-3-oxide (PTIO) shows the opposite effect. At the same time, these NO modulators fail to affect Bcl-2 phosphorylation, suggesting that NO regulates Bcl-2 stability in a phosphorylation-independent manner. In addition, Bcl-2 S-nitrosylation reduction induced by ZD55-IL-24 was attributed to both iNOS decrease and TrxR1 increase. iNOS-siRNA facilitates Bcl-2 S-denitrosylation and ubiquitin-degradation, whereas the TrxR1 inhibitor auranofin prevents Bcl-2 from denitrosylation and ubiquitination, thus restrains the caspase signal pathway activation and subsequent cancer cell apoptosis. Taken together, our studies reveal that MDA-7/IL-24 induces Bcl-2 S-denitrosylation via regulation of iNOS and TrxR1. Moreover, denitrosylation of Bcl-2 results in its ubiquitination and subsequent caspase protease family activation, as a consequence, apoptosis susceptibility. These findings provide a novel insight into MDA-7/IL-24 induced growth inhibition and carcinoma apoptosis.

• Authors: Hui Tian, Jing Wang, BaoFu Zhang, JieHui Di, FeiFei Chen, HuiZhong Li, LianTao Li, DongSheng Pei, JunNian Zheng
• Journal: PloS one (PLoS One) Vol. 7 Issue 5 Pg. e37200 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22629368 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukins
• Nitric Oxide Donors
• Proto-Oncogene Proteins c-bcl-2
• RNA, Small Interfering
• Ubiquitin
• interleukin-24
• Nitroprusside
• Proteasome Endopeptidase Complex
• ATP dependent 26S protease

Topics

• Apoptosis (drug effects, physiology)
• Cell Line, Tumor
• Cell Survival (drug effects, physiology)
• HeLa Cells
• Humans
• Interleukins (genetics, metabolism)
• Neoplasms (enzymology, metabolism)
• Nitric Oxide Donors (pharmacology)
• Nitroprusside (pharmacology)
• Phosphorylation (drug effects, genetics)
• Proteasome Endopeptidase Complex (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• RNA, Small Interfering
• Signal Transduction (drug effects, genetics)
• Ubiquitin (genetics, metabolism)