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1.
Nat Cancer ; 1(9): 894-908, 2020 09.
Article in English | MEDLINE | ID: mdl-35121952

ABSTRACT

Argininosuccinate synthase (ASS1) downregulation in different tumors has been shown to support cell proliferation and yet, in several common cancer subsets ASS1 expression associates with poor patient prognosis. Here we demonstrate that ASS1 expression under glucose deprivation is induced by c-MYC, providing survival benefit by increasing nitric oxide synthesis and activating the gluconeogenic enzymes pyruvate carboxylase and phosphoenolpyruvate carboxykinase by S-nitrosylation. The resulting increased flux through gluconeogenesis enhances serine, glycine and subsequently purine synthesis. Notably, high ASS1-expressing breast cancer mice do not respond to immune checkpoint inhibitors and patients with breast cancer with high ASS1 have more metastases. We further find that inhibiting purine synthesis increases pyrimidine to purine ratio, elevates expression of the immunoproteasome and significantly enhances the response of autologous primary CD8+ T cells to anti-PD-1. These results suggest that treating patients with high-ASS1 cancers with purine synthesis inhibition is beneficial and may also sensitize them to immune checkpoint inhibition therapy.


Subject(s)
Argininosuccinate Synthase , Breast Neoplasms , Animals , Argininosuccinate Synthase/metabolism , CD8-Positive T-Lymphocytes/metabolism , Cell Line, Tumor , Female , Humans , Immune Checkpoint Inhibitors , Mice , Purines
2.
Sci Rep ; 8(1): 59, 2018 01 08.
Article in English | MEDLINE | ID: mdl-29311649

ABSTRACT

microRNAs (miRNAs) are critical for neuronal function and their dysregulation is repeatedly observed in neurodegenerative diseases. Here, we implemented high content image analysis for investigating the impact of several miRNAs in mouse primary motor neurons. This survey directed our attention to the neuron-specific miR-124, which controls axonal morphology. By performing next generation sequencing analysis and molecular studies, we characterized novel roles for miR-124 in control of mitochondria localization and function. We further demonstrated that the intermediate filament Vimentin is a key target of miR-124 in this system. Our data establishes a new pathway for control of mitochondria function in motor neurons, revealing the value of a neuron-specific miRNA gene as a mechanism for the re-shaping of otherwise ubiquitously-expressed intermediate filament network, upstream of mitochondria activity and cellular metabolism.


Subject(s)
Gene Expression Regulation , MicroRNAs/genetics , Mitochondria/genetics , Mitochondria/metabolism , Motor Neurons/metabolism , RNA Interference , Vimentin/genetics , Animals , Axons , Cells, Cultured , Computational Biology/methods , Gene Expression Profiling , Gene Ontology , Mice , Molecular Imaging , Transcriptome , Vimentin/metabolism
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