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Mitochondrial complex i activity and nad(+)/nadh balance regulate breast cancer progression

Academic Article
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Overview

related to degree

  • LeBoeuf, Sarah, Ph.D. in Biology, Scripps Research 2010 - 2015
  • Gay, Laurie, Ph.D. in Biology, Scripps Research 2008 - 2014

authors

  • Santidrian, A. F.
  • Matsuno-Yagi, A.
  • Ritland, M.
  • Seo, B. B.
  • LeBoeuf, Sarah
  • Gay, Laurie
  • Yagi, Takao
  • Felding, Brunhilde

publication date

  • March 2013

journal

  • Journal of Clinical Investigation  Journal

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.

subject areas

  • Acrylamides
  • Animals
  • Autophagy
  • Brain Neoplasms
  • Cell Line, Tumor
  • Cell Proliferation
  • Cytokines
  • Disease Progression
  • Electron Transport Complex I
  • Female
  • Gene Knockdown Techniques
  • Humans
  • Lung Neoplasms
  • Mammary Neoplasms, Experimental
  • Mice
  • Mice, Inbred BALB C
  • Mice, SCID
  • Microtubule-Associated Proteins
  • Mitochondria
  • Multiprotein Complexes
  • NAD
  • Neoplasm Transplantation
  • Niacin
  • Niacinamide
  • Nicotinamide Phosphoribosyltransferase
  • Piperidines
  • Protein Transport
  • Proteins
  • Recombinant Proteins
  • Saccharomyces cerevisiae Proteins
  • TOR Serine-Threonine Kinases
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Identity

PubMed Central ID

  • PMC3582128

International Standard Serial Number (ISSN)

  • 0021-9738

Digital Object Identifier (DOI)

  • 10.1172/jci64264

PubMed ID

  • 23426180
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Additional Document Info

start page

  • 1068

end page

  • 1081

volume

  • 123

issue

  • 3

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