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.
Subject(s)
Breast Neoplasms/pathology , DEAD-box RNA Helicases/metabolism , Mitochondria/metabolism , Protein Biosynthesis/drug effects , Radiation-Sensitizing Agents/pharmacology , Azepines/pharmacology , Azepines/therapeutic use , Breast/pathology , Breast Neoplasms/mortality , Breast Neoplasms/therapy , Cell Line, Tumor , DEAD-box RNA Helicases/antagonists & inhibitors , DEAD-box RNA Helicases/genetics , Down-Regulation , Female , Gene Knockdown Techniques , Humans , Imidazoles/pharmacology , Imidazoles/therapeutic use , Mitochondria/drug effects , Mitochondria/genetics , Mitochondria/radiation effects , Oncogenes/drug effects , Proteomics , Radiation-Sensitizing Agents/therapeutic use , Reactive Oxygen Species/metabolism , Reactive Oxygen Species/radiation effects , Survival AnalysisSubject(s)
Carcinoma, Squamous Cell/genetics , DEAD-box RNA Helicases/genetics , Mouth Neoplasms/genetics , Female , Humans , MaleABSTRACT
BACKGROUND: Preoperative CT-angiography (CTA) has shown to reduce operative time in deep inferior epigastric perforator (DIEP) flap breast reconstruction compared to Doppler ultrasonography (US). Although decreased flap loss has been suggested, statistical significant reduction remains indeterminate. The purpose of this review is to evaluate flap loss after preoperative CTA and Doppler US in DIEP-flap breast reconstruction. METHODS: A systematic literature search was performed in MEDLINE, EMBASE, and Cochrane libraries. All articles comparing CTA to Doppler US were selected and critically appraised; data on flap loss were extracted. RESULTS: From 678 studies, eight were selected for appraisal. Six case-control studies were included in the final analysis. Pooled analysis showed CTA resulted in a significant reduction in partial necrosis (odds ratio/OR 0.15; 95% confidence interval/CI 0.07-0.32, P < 0.0001) and decreased flap loss (OR 0.28; 95% CI 0.10-0.79, P = 0.02). CONCLUSIONS: Studies included in this meta-analysis have several limitations. However, most studies find a large clinical advantage of CTA over Doppler US, which reaches statistical significance when combined. As results show that CTA prior to DIEP flap breast reconstruction offers significant clinical benefits, we suggest the routine use of preoperative CTA.
