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RUNX3 enhances TRAIL-induced apoptosis by upregulating DR5 in colorectal cancer
Oncogene ( IF 6.9 ) Pub Date : 2019-01-28 , DOI: 10.1038/s41388-019-0693-x
Bo Ram Kim , Seong Hye Park , Yoon A Jeong , Yoo Jin Na , Jung Lim Kim , Min Jee Jo , Soyeon Jeong , Hye Kyeong Yun , Sang Cheul Oh , Dae-Hee Lee

RUNX3 is frequently inactivated by DNA hypermethylation in numerous cancers. Here, we show that RUNX3 has an important role in modulating apoptosis in immediate response to tumor necrosis factor-related apoptosis-including ligand (TRAIL). Importantly, no combined effect of TRAIL and RUNX3 was observed in non-cancerous cells. We investigated the expression of the death receptors (DRs) DR4 and DR5, which are related to TRAIL resistance. Overexpression of RUNX3 increased DR5 expression via induction of the reactive oxygen species (ROS)-endoplasmic reticulum (ER) stress-effector CHOP. Reduction of DR5 markedly decreased apoptosis enhanced by the combined therapy of TRAIL and RUNX3. Interestingly, RUNX3 induced reactive oxygen species production by inhibiting SOD3 transcription via binding to the Superoxide dismutase 3 (SOD3) promoter. Additionally, the combined effect of TRAIL and RUNX3 decreased tumor growth in xenograft models. Our results demonstrate a direct role for RUNX3 in TRAIL-induced apoptosis via activation of DR5 and provide further support for RUNX3 as an anti-tumor.



中文翻译:

RUNX3通过上调大肠癌DR5增强TRAIL诱导的细胞凋亡

在许多癌症中,RUNX3经常被DNA高甲基化灭活。在这里,我们显示RUNX3在调节细胞凋亡中对肿瘤坏死因子相关的凋亡-包括配体(TRAIL)的立即反应中起着重要的作用。重要的是,在非癌细胞中未观察到TRAIL和RUNX3的联合作用。我们调查了死亡受体(DRs)DR4和DR5的表达,它们与TRAIL抗性有关。RUNX3的过表达通过诱导活性氧(ROS)-内质网(ER)应激效应CHOP来增加DR5表达。DR5的减少明显降低了TRAIL和RUNX3的联合治疗所增强的凋亡。有趣的是,RUNX3通过与超氧化物歧化酶3(SOD3)启动子结合来抑制SOD3转录,从而诱导了活性氧的产生。此外,TRAIL和RUNX3的共同作用降低了异种移植模型中的肿瘤生长。我们的结果表明,RUNX3通过激活DR5在TRAIL诱导的细胞凋亡中具有直接作用,并为RUNX3作为抗肿瘤药物提供了进一步的支持。

更新日期:2019-01-29
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