title: Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression.
abstract: Despite advances in clinical therapy, metastasis remains the leading cause of death in breast cancer patients. Mutations in mitochondrial DNA, including those affecting complex I and oxidative phosphorylation, are found in breast tumors and could facilitate metastasis. This study identifies mitochondrial complex I as critical for defining an aggressive phenotype in breast cancer cells. Specific enhancement of mitochondrial complex I activity inhibited tumor growth and metastasis through regulation of the tumor cell NAD+/NADH redox balance, mTORC1 activity, and autophagy. Conversely, nonlethal reduction of NAD+ levels by interfering with nicotinamide phosphoribosyltransferase expression rendered tumor cells more aggressive and increased metastasis. The results translate into a new therapeutic strategy: enhancement of the NAD+/NADH balance through treatment with NAD+ precursors inhibited metastasis in xenograft models, increased animal survival, and strongly interfered with oncogene-driven breast cancer progression in the MMTV-PyMT mouse model. Thus, aberration in mitochondrial complex I NADH dehydrogenase activity can profoundly enhance the aggressiveness of human breast cancer cells, while therapeutic normalization of the NAD+/NADH balance can inhibit metastasis and prevent disease progression.
authors: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.
authors: Antonio F
authors: AF
authors: Santidrian
authors: Akemi
authors: A
authors: Matsuno-Yagi
authors: Melissa
authors: M
authors: Ritland
authors: Byoung B
authors: BB
authors: Seo
authors: Sarah E
authors: SE
authors: LeBoeuf
authors: Laurie J
authors: LJ
authors: Gay
authors: Takao
authors: T
authors: Yagi
authors: Brunhilde
authors: B
authors: Felding-Habermann
mesh_terms: D000178:Acrylamides / Q000494:pharmacology; D000818:Animals; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D001932:Brain Neoplasms / Q000378:metabolism* / Q000556:secondary; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D018450:Disease Progression; D042967:Electron Transport Complex I / Q000096:biosynthesis / Q000502:physiology*; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D046912:Multiprotein Complexes; D009243:NAD / Q000378:metabolism* / Q000502:physiology; D009368:Neoplasm Transplantation; D009525:Niacin / Q000494:pharmacology; D009536:Niacinamide / Q000494:pharmacology; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D021381:Protein Transport; D011506:Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis; D029701:Saccharomyces cerevisiae Proteins / Q000096:biosynthesis / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases
chemical_list: C502778:ATG5 protein, human; D000178:Acrylamides; D000071187:Autophagy-Related Protein 5; D016207:Cytokines; D008869:Microtubule-Associated Proteins; D046912:Multiprotein Complexes; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; C493237:Ndi1 protein, S cerevisiae; D010880:Piperidines; D011506:Proteins; D011994:Recombinant Proteins; D029701:Saccharomyces cerevisiae Proteins; D009243:NAD; D009536:Niacinamide; D009525:Niacin; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D042967:Electron Transport Complex I