TITLE

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

AUTHOR(S)
Santidrian, Antonio F.; Matsuno-Yagi, Akemi; Ritiand, Melissa; Seo, Byoung B.; LeBoeuf, Sarah E.; Gay, Laurie J.; Yagi, Takao; Felding-Habermann, Brunhilde
PUB. DATE
March 2013
SOURCE
Journal of Clinical Investigation;Mar2013, Vol. 123 Issue 3, p1068
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
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, mTORCl activity, and autophagy. Conversely, nonlethal reduction of NAD+ levels by inter-fering 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.
ACCESSION #
85973872

 

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