MDA-7/IL-24 induces Bcl-2 denitrosylation and ubiquitin-degradation involved in cancer cell apoptosis.
MDA-7/IL-24 induces Bcl-2 denitrosylation and ubiquitin-degradation involved in cancer cell apoptosis.
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MDA-7/IL-24 诱导参与癌细胞凋亡的 Bcl-2 去亚硝基化和泛素降解
DOI：
10.1371/journal.pone.0037200
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Zheng J
中科院分区：
文献类型：
--
作者：
Tian H;Wang J;Zhang B;Di J;Chen F;Li H;Li L;Pei D;Zheng J
MDA-7/IL-24通过抑制线粒体死亡通路的关键凋亡调节蛋白Bcl-2的表达，参与肿瘤特异性凋亡。然而，这种监管的潜在机制尚不清楚。我们在这里报道了肿瘤选择性复制腺病毒ZD55-IL-24导致Bcl-2 s -脱硝基化和伴随的泛素化，这参与了26S蛋白酶体的降解。IL-24- sirna通过逆转Bcl-2 s -脱硝基化完全阻断Bcl-2泛素化，保护Bcl-2免受蛋白酶体降解，证实了MDA-7/IL-24在肿瘤细胞中调控Bcl-2翻译后修饰的重要作用。一氧化氮（NO）是蛋白质s -亚硝基化和脱硝基化的关键调节因子。NO供体硝普钠（SNP）下调Bcl-2 s -脱硝基化，减弱Bcl-2泛素化，从而抵消MDA-7/IL-24诱导的癌细胞凋亡，而NO抑制剂2-（4-羧基苯基）-4,4,5,5-四甲基咪唑啉-1-氧-3-氧化物（PTIO）则表现出相反的作用。同时，这些NO调节剂不能影响Bcl-2的磷酸化，表明NO以磷酸化不依赖的方式调节Bcl-2的稳定性。此外，ZD55-IL-24诱导的Bcl-2 s -亚硝基化降低与iNOS减少和TrxR1增加有关。iNOS-siRNA促进Bcl-2 s -脱硝基化和泛素降解，而TrxR1抑制剂auranofin则阻止Bcl-2的脱硝基化和泛素化，从而抑制caspase信号通路的激活和随后的癌细胞凋亡。综上所述，我们的研究表明MDA-7/IL-24通过调控iNOS和TrxR1诱导Bcl-2 s -脱硝。此外，Bcl-2的脱硝基化导致其泛素化和随后的caspase蛋白酶家族激活，从而导致细胞凋亡易感性。这些发现为MDA-7/IL-24诱导的生长抑制和癌细胞凋亡提供了新的见解。
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.
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影响因子：
4.8
作者：
Azad, Neelam;Vallyathan, Val;Rojanasakul, Yon
通讯作者：
Rojanasakul, Yon
影响因子：
11.4
作者：
Grandgirard, D;Studer, E;Michel, MR
通讯作者：
Michel, MR
影响因子：
56.9
作者：
Mannick, JB;Hausladen, A;Stamler, JS
通讯作者：
Stamler, JS
影响因子：
11.2
作者：
Lebedeva, IV;Sarkar, D;Fisher, PB
通讯作者：
Fisher, PB
DOI：
10.1165/rcmb.2009-0094oc
发表时间：
2010-05-01
影响因子：
6.4
作者：
Azad, Neelam;Iyer, Anand Krishnan V.;Rojanasakul, Yon
通讯作者：
Rojanasakul, Yon