Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression

J Clin Invest. 2013 Mar;123(3):1068-81. doi: 10.1172/JCI64264. Epub 2013 Feb 15.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acrylamides / pharmacology
  • Animals
  • Autophagy
  • Autophagy-Related Protein 5
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / secondary
  • Cell Line, Tumor
  • Cell Proliferation
  • Cytokines / antagonists & inhibitors
  • Cytokines / metabolism
  • Disease Progression
  • Electron Transport Complex I / biosynthesis
  • Electron Transport Complex I / physiology*
  • Female
  • Gene Knockdown Techniques
  • Humans
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / secondary
  • Mammary Neoplasms, Experimental / metabolism*
  • Mammary Neoplasms, Experimental / pathology
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Inbred BALB C
  • Mice, SCID
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Mitochondria / metabolism
  • Multiprotein Complexes
  • NAD / metabolism*
  • NAD / physiology
  • Neoplasm Transplantation
  • Niacin / pharmacology
  • Niacinamide / pharmacology
  • Nicotinamide Phosphoribosyltransferase / antagonists & inhibitors
  • Nicotinamide Phosphoribosyltransferase / metabolism
  • Piperidines / pharmacology
  • Protein Transport
  • Proteins / metabolism
  • Recombinant Proteins / biosynthesis
  • Saccharomyces cerevisiae Proteins / biosynthesis
  • Saccharomyces cerevisiae Proteins / physiology*
  • TOR Serine-Threonine Kinases

Substances

  • ATG5 protein, human
  • Acrylamides
  • Autophagy-Related Protein 5
  • Cytokines
  • Microtubule-Associated Proteins
  • Multiprotein Complexes
  • N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide
  • Ndi1 protein, S cerevisiae
  • Piperidines
  • Proteins
  • Recombinant Proteins
  • Saccharomyces cerevisiae Proteins
  • NAD
  • Niacinamide
  • Niacin
  • Nicotinamide Phosphoribosyltransferase
  • nicotinamide phosphoribosyltransferase, human
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Electron Transport Complex I