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Establishing Cell Lines Overexpressing DR3 to Assess the Apoptotic Response to Anti-mitotic Therapeutics
Published on: January 11, 2019
Targeting mitochondrial translation by inhibiting DDX3: a novel radiosensitization strategy for cancer treatment
M R Heerma van Voss1,2, F Vesuna1, G M Bol1,2
1Department of Radiology and Radiological Sciences, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.
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.
Insights
The DEAD box RNA helicase DDX3, targeted by RK-33, shows oncogenic properties in breast cancer. Inhibiting DDX3 with RK-33 disrupts mitochondrial translation, enhancing radiosensitization by causing a bioenergetic catastrophe.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- The DEAD box RNA helicase DDX3 possesses oncogenic properties.
- RK-33 is a novel small-molecule inhibitor of DDX3, demonstrating radiosensitizing effects in preclinical cancer models.
Purpose of the Study:
- To evaluate DDX3 as a therapeutic target in breast cancer.
- To investigate the anti-neoplastic mechanisms of RK-33.
Main Methods:
- Quantitative proteomics to identify protein changes after RK-33 treatment or DDX3 knockdown.
- Assessment of mitochondrial function, including oxygen consumption, ATP levels, and reactive oxygen species (ROS).
- Evaluation of DNA repair capacity post-treatment.
Main Results:
- High DDX3 expression in 35% of breast cancer samples correlated with aggressive disease and poor survival.
- RK-33 and DDX3 knockdown downregulated mitochondrial translation and respiratory electron transport proteins.
- DDX3 inhibition reduced mitochondrial translation, decreased oxygen consumption and ATP, and increased ROS.
- RK-33 counteracted radiation-induced increases in oxygen consumption and ATP, while impairing DNA repair.
Conclusions:
- DDX3 is a promising therapeutic target in breast cancer.
- RK-33-mediated DDX3 inhibition radiosensitizes breast cancer by disrupting mitochondrial translation.
- This leads to reduced oxidative phosphorylation, elevated ROS, and a bioenergetic collapse, enhancing anti-cancer effects.
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