Redox Imbalance Prompts Breast Tumor Spread

Cancer researchers have found that the progression of breast tumors to a more aggressive stage with more likelihood to metastasize depends on mitochondrial complex I activity and the tumor cells' NAD+/NADH redox balance.

Investigators at the Scripps Research Institute (La Jolla, CA, USA) based their study on earlier findings indicating that mutations in mitochondrial DNA, including those affecting complex I and oxidative phosphorylation, were found in breast tumors and could facilitate metastasis.

In the current study, the investigators worked with cultures of human breast cancer cells and with a mouse breast cancer xenograft model. The investigators used a unique approach to define contributions of complex I activity to breast cancer progression, based on expression of the yeast NADH dehydrogenase Ndi1enzyme in human tumor cells. The Ndi1 gene encodes a single protein that faces the inner mitochondrial matrix and oxidizes NADH from the Krebs cycle. Ndi1 contains 26 N-terminal residues for mitochondrial import, can be functionally expressed in mammalian cells, and does not cause an immune response. Ndi1 restores complex I function in diseased cells, e.g., in neurons of Parkinson’s disease and optic neuropathy; protects cardiomyocytes from ischemic reperfusion injury; and increases lifespan in Drosophila.

Results published in the February 15, 2013, online edition of the Journal of Clinical Investigation revealed that specific enhancement of mitochondrial complex I activity inhibited tumor growth and metastasis through regulation of the tumor cell NAD+/NADH redox balance, mTORC1 (mammalian target of rapamycin) activity, and autophagy. Conversely, nonlethal reduction of NAD+ levels by interfering with nicotinamide phosphoribosyltransferase expression rendered tumor cells more aggressive and increased metastasis. 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.

"We already know the precursors can be easily ingested. It is not a totally new treatment that would need to be tested for toxicity and side effects like a new drug," said senior author Dr. Brunhilde Felding-Habermann, associate professor of chemical physiology at the Scripps Research Institute. "In animal models at various stages, we see that we can actually prevent progression of the disease."

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