Targeting mitochondrial translation by inhibiting DDX3: A novel radiosensitization strategy for cancer treatment
Heerma Van Voss, M. R.; Vesuna, F.; Bol, G. M.; Afzal, J.; Tantravedi, Saritha; Bergman, Y.; Kammers, Kai; Lehar, M.; Malek, Reem; Ballew, M.; ter Hoeve, N.; Abou, D.; Thorek, D.; Berlinicke, Cynthia; Yazdankhah, M.; Sinha, D.; le Couteur, A.; Abrahams, R.; Tran, Phuoc T.; Van Diest, P. J.; Raman, V.
(2018) Oncogene, volume 37, issue 1, pp. 63 - 74
(Article)
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
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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.
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Keywords: Molecular Biology, Genetics, Cancer Research
ISSN: 0950-9232
Publisher: Nature Publishing Group
Note: Funding Information: We thank Bob Cole, Tatiana Boronina and Bob O’ Meally of the Johns Hopkins Mass Spectrometry and Proteomics core facility for their help with the proteomics experiments; Tri Nguyen for his help with interpretation of the electron microscopy images; the Dawson Laboratory at the Johns Hopkins School of Medicine for their help with the mitochondrial translation assay; and Beth Rodgers, who kindly provided us with S35-methionine. This work was financially supported by Utrecht University Alexandre Suerman Stipend (MRHvV), the Dutch Cancer Foundation (UU2013-5851; MRHvV), NIH (R01CA166348 to PTT, R01CA193895 to AL, and R01CA140226 and R01CA131250 to VR), FAMRI (VR) and Safeway (VR). Publisher Copyright: © 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
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