Down-Regulation of NDUFB9 Promotes Breast Cancer Cell Proliferation, Metastasis by Mediating Mitochondrial Metabolism

• Published in: PloS one Vol. 10; no. 12; p. e0144441
• Main Authors: Li, Liang-Dong, Sun, He-Fen, Liu, Xue-Xiao, Gao, Shui-Ping, Jiang, Hong-Lin, Hu, Xin, Jin, Wei
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 07.12.2015; Public Library of Science (PLoS)
• Subjects: Abnormalities; AKT protein; Autophagy; Biomarkers; Blotting, Western; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cancer metastasis; Cell adhesion & migration; Cell Cycle; Cell growth; Cell migration; Cell Movement; Cell Proliferation; Chromatography; Data processing; Dehydrogenase; Dehydrogenases; Deoxyribonucleic acid; DNA; DNA, Mitochondrial - genetics; Down-Regulation; Electron transport chain; Epithelial-Mesenchymal Transition; Female; Gene expression; Gene Expression Regulation, Neoplastic; Genetic abnormalities; Genetic aspects; Humans; Immunoenzyme Techniques; Immunoglobulins; Laboratories; Metabolism; Metastases; Metastasis; Mitochondria; Mitochondria - metabolism; Mitochondria - pathology; Mitochondrial DNA; Motility; Mutation; NAD; NADH; NADH dehydrogenase; NADH Dehydrogenase - antagonists & inhibitors; NADH Dehydrogenase - genetics; NADH Dehydrogenase - metabolism; NADH-ubiquinone oxidoreductase; Nicotinamide adenine dinucleotide; Oncology; Oxidative Phosphorylation; Phosphorylation; Proteomics; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Small Interfering - genetics; Signal Transduction; Surgery; Tandem Mass Spectrometry; TOR protein; Tumor Cells, Cultured; United States > US; China
• DOI: 10.1371/journal.pone.0144441
• ISSN: 1932-6203

Despite advances in basic and clinical research, metastasis remains the leading cause of death in breast cancer patients. Genetic abnormalities in mitochondria, including mutations affecting complex I and oxidative phosphorylation, are found in breast cancers and might facilitate metastasis. Genes encoding complex I components have significant breast cancer prognostic value. In this study, we used quantitative proteomic analyses to compare a highly metastatic cancer cell line and a parental breast cancer cell line; and observed that NDUFB9, an accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I), was down-regulated in highly metastatic breast cancer cells. Furthermore, we demonstrated that loss of NDUFB9 promotes MDA-MB-231 cells proliferation, migration, and invasion because of elevated levels of mtROS, disturbance of the NAD+/NADH balance, and depletion of mtDNA. We also showed that, the Akt/mTOR/p70S6K signaling pathway and EMT might be involved in this mechanism. Thus, our findings contribute novel data to support the hypothesis that misregulation of mitochondrial complex I NADH dehydrogenase activity can profoundly enhance the aggressiveness of human breast cancer cells, suggesting that complex I deficiency is a potential and important biomarker for further basic research or clinical application.