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

作者：Santidrian, Antonio F.; Matsuno-Yagi, Akemi; Ritland, Melissa; Seo, Byoung B.; LeBoeuf, Sarah E.; Gay, Laurie J.; Yagi, Takao; Felding-Habermann, Brunhilde^*

来源：Journal of Clinical Investigation, 2013, 123(3): 1068-1081.

DOI：10.1172/JCI64264

• NADH-QUINONE OXIDOREDUCTASE
• DNA MUTATIONS
• TRANSCRIPTIONAL REGULATION
• SACCHAROMYCES-CEREVISIAE
• MAMMARY-TUMORS
• AUTOPHAGY
• SIRT1
• DYSFUNCTION
• EXPRESSION
• DEFECTS

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 anew 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.

• 出版日期2013-3