Difference between revisions of "Santidrian 2013 J Clin Invest"

Revision as of 14:56, 12 August 2013

Santidrian AF, Matsuno-Yagi A, Ritland M, Seo BB, Leboeuf SE, Gay LJ, Yagi T, Felding-Habermann B (2013) Mitochondrial Complex I activity and NAD+/NADH balance regulate breast cancer progression. J Clin Invest 123: 1068-1081

» PMID: 23426180 Open Access

Santidrian AF, Matsuno-Yagi A, Ritland M, Seo BB, Leboeuf SE, Gay LJ, Yagi T, Felding-Habermann B (2013) J Clin Invest

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. • Keywords: Metastasis, NAD+/NADH redox balance, mTORC1, Autophagy

• O2k-Network Lab: US CA La Jolla Felding-Habermann B

Labels: MiParea: Respiration, mtDNA;mt-genetics, Genetic knockout;overexpression, mt-Medicine Pathology: Cancer

Organism: Mouse

Preparation: Intact cells Enzyme: Complex I, Complex III

Coupling state: ROUTINE

HRR: Oxygraph-2k

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 {{Publication
-|title=Santidrian AF, Matsuno-Yagi A, Ritland M, Seo BB, Leboeuf SE, Gay LJ, Yagi T, Felding-Habermann B (2013) Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression. J Clin Invest 123: 1068-1081
+|title=Santidrian AF, Matsuno-Yagi A, Ritland M, Seo BB, Leboeuf SE, Gay LJ, Yagi T, Felding-Habermann B (2013) Mitochondrial Complex I activity and NAD+/NADH balance regulate breast cancer progression. J Clin Invest 123: 1068-1081
 |info=[http://www.ncbi.nlm.nih.gov/pubmed/23426180 PMID: 23426180 Open Access]
 |authors=Santidrian AF, Matsuno-Yagi A, Ritland M, Seo BB, Leboeuf SE, Gay LJ, Yagi T, Felding-Habermann B
 |year=2013
 |journal=J Clin Invest
-|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.
+|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.
 |keywords=Metastasis, NAD+/NADH redox balance, mTORC1, Autophagy,
 |mipnetlab=US CA La Jolla Felding-Habermann B
 }}
 {{Labeling
+|area=Respiration, mtDNA;mt-genetics, Genetic knockout;overexpression, mt-Medicine
 |organism=Mouse
 |preparations=Intact cells
 |enzymes=Complex I, Complex III
-|injuries=Cancer; Apoptosis; Cytochrome c, Genetic Defect; Knockdown; Overexpression
+|diseases=Cancer
 |couplingstates=ROUTINE
 |instruments=Oxygraph-2k
 }}