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, Debasish Sinha, A. Le, R. Abrahams, P. T. Tran, Paulus Joannes van DiestV. Raman

Research output: Contribution to journalArticle

Abstract

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 languageEnglish (US)
Pages (from-to)63-74
Number of pages12
JournalOncogene
Volume37
Issue number1
DOIs
StatePublished - Jan 4 2018

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Fingerprint Dive into the research topics of 'Targeting mitochondrial translation by inhibiting DDX3: A novel radiosensitization strategy for cancer treatment'. Together they form a unique fingerprint.

  • Cite this

    Heerma Van Voss, M. R., Vesuna, F., Bol, G. M., Afzal, J., Tantravedi, S., Bergman, Y., Kammers, K., Lehar, M., Malek, R., Ballew, M., Ter Hoeve, N., Abou, D., Thorek, D., Berlinicke, C., Yazdankhah, M., Sinha, D., Le, A., Abrahams, R., Tran, P. T., ... Raman, V. (2018). Targeting mitochondrial translation by inhibiting DDX3: A novel radiosensitization strategy for cancer treatment. Oncogene, 37(1), 63-74. https://doi.org/10.1038/onc.2017.308