Title |
Targeting mitochondrial translation by inhibiting DDX3: a novel radiosensitization strategy for cancer treatment
|
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Published in |
Oncogene, September 2017
|
DOI | 10.1038/onc.2017.308 |
Pubmed ID | |
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 |
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.Oncogene advance online publication, 4 September 2017; doi:10.1038/onc.2017.308. |
X Demographics
Geographical breakdown
Country | Count | As % |
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Unknown | 3 | 100% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 3 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Unknown | 82 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Researcher | 14 | 17% |
Student > Ph. D. Student | 13 | 16% |
Student > Bachelor | 7 | 9% |
Student > Master | 5 | 6% |
Other | 4 | 5% |
Other | 12 | 15% |
Unknown | 27 | 33% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 22 | 27% |
Agricultural and Biological Sciences | 6 | 7% |
Medicine and Dentistry | 5 | 6% |
Chemistry | 5 | 6% |
Immunology and Microbiology | 3 | 4% |
Other | 12 | 15% |
Unknown | 29 | 35% |