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

M. R. Heerma Van Voss, Farhad Vesuna, G. M. Bol, J. Afzal, S. Tantravedi, Y. Bergman, Kai Kammers, Mohamed Lehar, R. Malek, M. Ballew, N. Ter Hoeve, Diane Abou, D. Thorek, Cynthia Ann Berlinicke, M. Yazdankhah, D. Sinha, Quy Hoa Le Thi, R. Abrahams, Phuoc T Tran, P. J. Van DiestVenu 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

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Breast Neoplasms
Oxygen Consumption
Reactive Oxygen Species
Respiratory Transport
DEAD-box RNA Helicases
Adenosine Triphosphate
Neoplasms
Oxidative Phosphorylation
Electron Transport
Ionizing Radiation
DNA Repair
Proteomics
Energy Metabolism
Mitochondria
Therapeutics
Down-Regulation
Survival
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Targeting mitochondrial translation by inhibiting DDX3 : A novel radiosensitization strategy for cancer treatment. / Heerma Van Voss, M. R.; Vesuna, Farhad; Bol, G. M.; Afzal, J.; Tantravedi, S.; Bergman, Y.; Kammers, Kai; Lehar, Mohamed; Malek, R.; Ballew, M.; Ter Hoeve, N.; Abou, Diane; Thorek, D.; Berlinicke, Cynthia Ann; Yazdankhah, M.; Sinha, D.; Le Thi, Quy Hoa; Abrahams, R.; Tran, Phuoc T; Van Diest, P. J.; Raman, Venu.

In: Oncogene, Vol. 37, No. 1, 04.01.2018, p. 63-74.

Research output: Contribution to journalArticle

Heerma Van Voss, MR, Vesuna, F, Bol, GM, Afzal, J, Tantravedi, S, Bergman, Y, Kammers, K, Lehar, M, Malek, R, Ballew, M, Ter Hoeve, N, Abou, D, Thorek, D, Berlinicke, CA, Yazdankhah, M, Sinha, D, Le Thi, QH, Abrahams, R, Tran, PT, Van Diest, PJ & Raman, V 2018, 'Targeting mitochondrial translation by inhibiting DDX3: A novel radiosensitization strategy for cancer treatment', Oncogene, vol. 37, no. 1, pp. 63-74. https://doi.org/10.1038/onc.2017.308
Heerma Van Voss, M. R. ; Vesuna, Farhad ; Bol, G. M. ; Afzal, J. ; Tantravedi, S. ; Bergman, Y. ; Kammers, Kai ; Lehar, Mohamed ; Malek, R. ; Ballew, M. ; Ter Hoeve, N. ; Abou, Diane ; Thorek, D. ; Berlinicke, Cynthia Ann ; Yazdankhah, M. ; Sinha, D. ; Le Thi, Quy Hoa ; Abrahams, R. ; Tran, Phuoc T ; Van Diest, P. J. ; Raman, Venu. / Targeting mitochondrial translation by inhibiting DDX3 : A novel radiosensitization strategy for cancer treatment. In: Oncogene. 2018 ; Vol. 37, No. 1. pp. 63-74.
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