TY - JOUR
T1 - Targeting mitochondrial translation by inhibiting DDX3
T2 - A novel radiosensitization strategy for cancer treatment
AU - Heerma Van Voss, M. R.
AU - Vesuna, F.
AU - Bol, G. M.
AU - Afzal, J.
AU - Tantravedi, S.
AU - Bergman, Y.
AU - Kammers, K.
AU - Lehar, M.
AU - Malek, R.
AU - Ballew, M.
AU - Ter Hoeve, N.
AU - Abou, D.
AU - Thorek, D.
AU - Berlinicke, C.
AU - Yazdankhah, M.
AU - Sinha, D.
AU - Le, A.
AU - Abrahams, R.
AU - Tran, P. T.
AU - Van Diest, P. J.
AU - Raman, V.
N1 - Publisher Copyright:
© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
PY - 2018/1/4
Y1 - 2018/1/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85040164257&partnerID=8YFLogxK
U2 - 10.1038/onc.2017.308
DO - 10.1038/onc.2017.308
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C2 - 28869602
AN - SCOPUS:85040164257
SN - 0950-9232
VL - 37
SP - 63
EP - 74
JO - Oncogene
JF - Oncogene
IS - 1
ER -
