Abstract
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.
Highlights
Despite great achievements in clinical therapy, metastasis is still the leading cause of death in breast cancer patients. [1] A more comprehensive understanding of the cellular and molecular mechanisms that drive metastasis is vital for the development of more effective therapies
Using online “Kaplan Meier plotter” (KM plotter) database, in which updated gene expression data and survival information are supported for a total of 4142 breast cancer patients, we found that the majority of other subunits (NDUFB1-8/11) of the Nicotinamide Adenine Dinucleotide Hydrogen (NADH) dehydrogenase family had significant prognostic value (DMFS) for breast cancer patients [17] (S1 Fig and Table C in S1 File)
Using the iTRAQ labeling method in our model system, we found that NADH dehydrogenase beta sub-complex (NDUFB9) expression was slightly suppressed in MDA-MB-231HM cells compared to MDA-MB-231 cells (Fig 1A– 1D)
Summary
Despite great achievements in clinical therapy, metastasis is still the leading cause of death in breast cancer patients. [1] A more comprehensive understanding of the cellular and molecular mechanisms that drive metastasis is vital for the development of more effective therapies. [1] A more comprehensive understanding of the cellular and molecular mechanisms that drive metastasis is vital for the development of more effective therapies. LeBleu demonstrated that circulating cancer cells (CTCs) exhibit enhanced mitochondria biogenesis and respiration.[3] Other studies have shown that CTCs can be protected by aerobic glycolysis.[4] playing a dual role in tumors, reactive oxygen species (ROS) are produced mainly by mitochondria, [5] and contributes to malignancy by participating in molecular and cellular events involving cytoskeletal rearrangements, regulation of signaling pathways and transcriptional activities that favor cell migration, invasion and antiapoptosis.[6] In addition to mitochondrial DNA (mtDNA) mutations resulting from ROS that can lead to the progression of cancer, [7] altered mitochondrial DNA content is correlated with malignant potential in various cancers.[8]
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