Targeting mitochondrial translation by inhibiting DDX3: a novel radiosensitization strategy for cancer treatment
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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.
F Vesuna,G M Bol,J Afzal
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