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

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 DiestV. Raman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

50 Scopus citations


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.

Original languageAmerican English
Pages (from-to)63-74
Number of pages12
Issue number1
StatePublished - 4 Jan 2018
Externally publishedYes

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