新型放疗增敏法:抑制DDX3
  • 35%乳腺癌样本高表达DDX3,侵袭性高,生存期缩短;
  • 采用定量蛋白质组学方法,鉴定出参与线粒体翻译和呼吸电子传递通路的蛋白质,RK-33处理或敲除DDX3后明显下调;
  • DDX3位于线粒体,RK-33抑制DDX3后减少线粒体翻译,致氧耗率和细胞内ATP浓度下降、活性氧自由基(ROS)增加,RK-33拮抗氧耗量增加,抑制DNA修复;
  • RK-33抑制DDX3通过抑制线粒体翻译,使乳腺癌对放疗敏感性增强,导致氧化磷酸化能力下降,增加ROS水平,最终生物能量耗竭。
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Oncogene [IF:7.971]

Targeting mitochondrial translation by inhibiting DDX3: a novel radiosensitization strategy for cancer treatment

通过抑制DDX3靶向线粒体翻译:新的放疗增敏方法

10.1038/onc.2017.308

2017-09-04, Article

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DDX3 is a DEAD box RNA helicase with oncogenic properties. RK-33 is developed as a small-molecule inhibitor of DDX3 and showed potent radiosensitizing activity in preclinical tumor models. This study aimed to assess DDX3 as a target in breast cancer and to elucidate how RK-33 exerts its anti-neoplastic effects. High DDX3 expression was present in 35% of breast cancer patient samples and correlated with markers of aggressiveness and shorter survival. With a quantitative proteomics approach, we identified proteins involved in the mitochondrial translation and respiratory electron transport pathways to be significantly downregulated after RK-33 or DDX3 knockdown. DDX3 localized to the mitochondria and DDX3 inhibition with RK-33 reduced mitochondrial translation. As a consequence, oxygen consumption rates and intracellular ATP concentrations decreased and reactive oxygen species (ROS) increased. RK-33 antagonized the increase in oxygen consumption and ATP production observed after exposure to ionizing radiation and reduced DNA repair. Overall, we conclude that DDX3 inhibition with RK-33 causes radiosensitization in breast cancer through inhibition of mitochondrial translation, which results in reduced oxidative phosphorylation capacity and increased ROS levels, culminating in a bioenergetic catastrophe.Oncogene advance online publication, 4 September 2017; doi:10.1038/onc.2017.308.

First Authors:
F Vesuna,G M Bol,J Afzal

Correspondence Authors:
V Raman

All Authors:
M R Heerma van Voss,F Vesuna,G M Bol,J Afzal,S Tantravedi,Y Bergman,K Kammers,M Lehar,R Malek,M Ballew,N Ter Hoeve,D Abou,D Thorek,C Berlinicke,M Yazdankhah,D Sinha,A Le,R Abrahams,P T Tran,P J van Diest,V Raman

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