Cell Death Differ
Department of Biomedical Sciences, University of Padova, via U. Bassi 58/B, 35131, Padova, Italy.
Published: October 2022
Neurofibromin loss drives neoplastic growth and a rewiring of mitochondrial metabolism. Here we report that neurofibromin ablation dampens expression and activity of NADH dehydrogenase, the respiratory chain complex I, in an ERK-dependent fashion, decreasing both respiration and intracellular NAD. Expression of the alternative NADH dehydrogenase NDI1 raises NAD/NADH ratio, enhances the activity of the NAD-dependent deacetylase SIRT3 and interferes with tumorigenicity in neurofibromin-deficient cells. The antineoplastic effect of NDI1 is mimicked by administration of NAD precursors or by rising expression of the NAD deacetylase SIRT3 and is synergistic with ablation of the mitochondrial chaperone TRAP1, which augments succinate dehydrogenase activity further contributing to block pro-neoplastic metabolic changes. These findings shed light on bioenergetic adaptations of tumors lacking neurofibromin, linking complex I inhibition to mitochondrial NAD/NADH unbalance and SIRT3 inhibition, as well as to down-regulation of succinate dehydrogenase. This metabolic rewiring could unveil attractive therapeutic targets for neoplasms related to neurofibromin loss.
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http://dx.doi.org/10.1038/s41418-022-00991-4 | DOI Listing |
Cancers (Basel)
May 2022
Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
Germline mutations of cause neurofibromatosis type 1 () through the activation of the signaling pathway, and some patients develop malignant peripheral nerve sheath tumors (MPNSTs). Here, we established subclones of the human -MPNST cell line sNF96.2 that manifest increased tumorigenic activity and increased phosphorylation of the protein kinases MEK and Akt relative to the parental cells.
View Article and Find Full Text PDFCell Death Differ
October 2022
Department of Biomedical Sciences, University of Padova, via U. Bassi 58/B, 35131, Padova, Italy.
Cancer Cell
March 2020
Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. Electronic address:
We report that neurofibromin, a tumor suppressor and Ras-GAP (GTPase-activating protein), is also an estrogen receptor-α (ER) transcriptional co-repressor through leucine/isoleucine-rich motifs that are functionally independent of GAP activity. GAP activity, in turn, does not affect ER binding. Consequently, neurofibromin depletion causes estradiol hypersensitivity and tamoxifen agonism, explaining the poor prognosis associated with neurofibromin loss in endocrine therapy-treated ER breast cancer.
View Article and Find Full Text PDFInvest Ophthalmol Vis Sci
May 2018
Department of Pediatrics and Neonatal-Perinatal Medicine, Augusta University, Augusta, Georgia, United States.
Purpose: Neurofibromatosis type 1 (NF1) is the result of inherited mutations in the NF1 tumor suppressor gene, which encodes the protein neurofibromin. Eye manifestations are common in NF1 with recent reports describing a vascular dysplasia in the retina and choroid. Common features of NF1 retinopathy include tortuous and dilated feeder vessels that terminate in capillary tufts, increased endothelial permeability, and neovascularization.
View Article and Find Full Text PDFSci Rep
April 2018
Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, 160-8582, Japan.
Neurofibromatosis type 1 (NF1) is caused by germline mutations in the NF1 gene and is characterized by café au lait spots and benign tumours known as neurofibromas. NF1 encodes the tumour suppressor protein neurofibromin, which negatively regulates the small GTPase Ras, with the constitutive activation of Ras signalling resulting from NF1 mutations being thought to underlie neurofibroma development. We previously showed that knockdown of neurofibromin triggers epithelial-mesenchymal transition (EMT) signalling and that such signalling is activated in NF1-associated neurofibromas.
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