fk-866 and Brain-Neoplasms

The aggressive primary brain tumor glioblastoma (GBM) is characterized by aberrant metabolism that fuels its malignant phenotype. Diverse genetic subtypes of malignant glioma are sensitive to selective inhibition of the NAD

Topics: Acrylamides; Animals; Autophagy; B7-H1 Antigen; Brain Neoplasms; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Movement; Cyanides; Cytokines; Delayed-Action Preparations; Drug Carriers; Glioblastoma; Guanidines; Humans; Injections, Intralesional; Macrophages; Membrane Proteins; Mice; NAD; Nicotinamide Phosphoribosyltransferase; Piperidines; Polymers; RNA, Messenger; Signal Transduction; Tumor Microenvironment; Up-Regulation

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.

Topics: Acrylamides; Animals; Autophagy; Autophagy-Related Protein 5; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Cytokines; Disease Progression; Electron Transport Complex I; Female; Gene Knockdown Techniques; Humans; Lung Neoplasms; Mammary Neoplasms, Experimental; Mechanistic Target of Rapamycin Complex 1; 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