Overexpression of CYB5R3 and NQO1, two NAD+ producing enzymes, mimics aspects of caloric restriction
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PROVIDER: PRJNA425944 | ENA |
REPOSITORIES: ENA
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Project description:Calorie restriction (CR) is one of the most robust means to improve health and survival in model organisms. CR imposes a metabolic program that leads to increased stress resistance and delayed onset of chronic diseases, including cancer. In rodents, CR induces the upregulation of two NADH-dehydrogenases, namely NAD(P)H:quinone oxidoreductase 1 (Nqo1) and cytochrome b5 reductase 3 (Cyb5r3), which provide electrons for energy metabolism. It has been proposed that this upregulation may be responsible for some of the beneficial effects of CR, and defects in their activity are linked to aging and several age-associated diseases. However, it is unclear whether changes in metabolic homeostasis solely through up-regulation of these NADH-dehydrogenases have a positive impact on health and survival. We generated a mouse that overexpresses both metabolic enzymes leading to phenotypes that resemble aspects of CR including a modest increase in lifespan, greater physical performance, a decrease in chronic inflammation, and importantly, protection against carcinogenesis, one of the main hallmarks of CR. Furthermore, these animals showed an enhancement of metabolic flexibility and a significant upregulation of the NAD+/sirtuin pathway. The results highlight the importance of these NAD+ producers for the promotion of health and extended lifespan.
2018-07-31 | GSE108379 | GEO
Project description: Not available
| S-EPMC6052403 | biostudies-literature
Project description:Ferroptosis, an emerging nonapoptotic, regulated cell death process distinguished by iron accumulation and subsequent lipid peroxidation, is intricately implicated in the development and progression of multiple cancer types. Here, we aimed to reveal that triggering ferroptosis is a promising treatment strategy for ovarian cancer. In this study, we not only validated that daphnetin caused ferroptosis, but evaluated the effects of daphnetin (and/or cisplatin) in vitro and vivo.Here, we elucidated that daphnetin, a natural product isolated from Daphne Korean Nakai, can exert antitumor effects by inducing the death and suppressing the migration of ovarian cancer cells. Subsequently, transcriptome analysis and ferroptosis inhibitor (Fer-1 and DFO) experiments revealed that there is a close correlation between daphnetin and ferroptosis in ovarian cancer. We further found that daphnetin induced ferroptosis in ovarian cancer cells, as evidenced by the accumulation of intracellular ferrous iron (Fe2+), reactive oxygen species (ROS) and lipid peroxides, as well as the depletion of glutathione (GSH) and ferroptosis indicators (SLC7A11 and GPX4). In particular, daphnetin effectively reduced the mRNA and protein levels of NQO1 (a ubiquitous flavoenzyme), and a high expression level of NQO1 was significantly associated with poor prognosis and ferroptosis resistance in ovarian cancer patients. Furthermore, NQO1 activation markedly attenuated daphnetin-induced cell death, migration and ferroptotic events in vitro and vivo. Interestingly, we also found that treatment with daphnetin, a negative regulator of NQO1, in combination with cisplatin synergistically induced ovarian cancer cell cytotoxicity. This study demonstrated that daphnetin induces ferroptosis by inhibiting NQO1 in ovarian cancer cells. Our findings identified NQO1 as a new daphnetin target and suggested that targeting NQO1 might have therapeutic effects on ovarian cancer.
2024-05-23 | GSE267812 | GEO
Project description:NQO1 silencing by a specific shRNA against NQO1 increased migration and hormone-independent survival in hormone-dependent human prostate cancer cells LNCaP. Genome wide array revealed that NQO1 blockade significantly upregulated pro-inflammatory mediators (e.g., IL-32, CCL2, IL-8, IL-17C, IL-10RA, CXCR2, CXCR7, NOS3) associated with prostate tumorigenesis. Two-condition experiment, control vs. NQO1 knockdown LNCaP cells. Biological replicates: 3 control replicates, 3 NQO1 knockdown replicates.
2014-08-26 | E-GEOD-58336 | biostudies-arrayexpress
Project description:NQO1 silencing by a specific shRNA against NQO1 increased migration and hormone-independent survival in hormone-dependent human prostate cancer cells LNCaP. Genome wide array revealed that NQO1 blockade significantly upregulated pro-inflammatory mediators (e.g., IL-32, CCL2, IL-8, IL-17C, IL-10RA, CXCR2, CXCR7, NOS3) associated with prostate tumorigenesis.
2014-08-26 | GSE58336 | GEO
Project description:RNA-seq data were generated to characterize global gene expression differences, identify key differentially expressed genes, and explore the associated biological pathways and molecular mechanismsThis study aimed to investigate the expression and function of NAD(P)H:quinone oxidoreductase 1 (NQO1) during glycidyl methacrylate (GMA)-induced malignant transformation of lung epithelial cells and its association with oxidative stress-related signaling pathways.BEAS-2B cells were chronically exposed to GMA to establish a malignant transformation model (GMA-T50). Cell migration, invasion, and proliferation were assessed using wound-healing, Transwell, soft agar, and colony formation assays. Tumorigenicity was evaluated in nude mice with histopathology and immunohistochemistry. Transcriptomic sequencing and bioinformatics analyses were used to identify key molecules. NQO1 expression was measured by reverse transcription quantitative PCR and Western blotting. After siRNA-mediated NQO1 knockdown, proliferation, migration, invasion, and apoptosis were analyzed. Intracellular reactive oxygen species were detected using 2′,7′-dichlorodihydrofluorescein diacetate, and the nuclear factor erythroid 2–related factor 2/heme oxygenase-1 signaling pathway was examined, with N-acetyl-L-cysteine used to modulate oxidative stress. Long-term GMA exposure induced stable malignant phenotypes with increased migration, invasion, and proliferation and tumor formation in vivo. NQO1 mRNA and protein levels were markedly upregulated in transformed cells . NQO1 knockdown significantly suppressed proliferation, migration, and invasion and promoted apoptosis . GMA increased ROS and upregulated Nrf2, HO-1, and NQO1, whereas NAC reduced ROS and downregulated pathway proteins. NQO1 was also highly expressed in lung adenocarcinoma cells and tissues , suggesting that it may promote malignant progression through the ROS-mediated Nrf2/HO-1 pathway.
2026-05-20 | GSE331155 | GEO
Project description:NAD(P)H:quinone Oxidoreductase (NQO1) is essential for cell defense against reactive oxidative species, cancer, and metabolic stress. Recently, NQO1 was found in ribonucleoprotein (RNP) complexes, but NQO1-interacting mRNAs and the functional impact of such interactions are not known. Here, we used ribonucleoprotein immunoprecipitation (RIP) and microarray analysis to identify comprehensively the subset of NQO1 target mRNAs in human hepatoma HepG2 cells. One of its main targets, SERPINA1 mRNA, encodes the serine protease inhibitor α-1-antitrypsin, A1AT, which is associated with disorders including obesity-related metabolic inflammation, chronic obstructive pulmonary disease (COPD), liver cirrhosis and hepatocellular carcinoma. Biotin pulldown analysis indicated that NQO1 can bind the 3’ untranslated region (UTR) and the coding region (CR) of SERPINA1 mRNA. NQO1 did not affect SERPINA1 mRNA levels; instead, it enhanced the translation of SERPINA1 mRNA, as NQO1 silencing decreased the size of polysomes forming on SERPINA1 mRNA and lowered the abundance of A1AT. Luciferase reporter analysis further indicated that NQO1 regulates SERPINA1 mRNA translation through the SERPINA1 3’UTR. Accordingly, NQO1-KO mice had reduced hepatic and serum levels of A1AT and increased activity of neutrophil elastase, one of the main targets of A1AT. We propose that this novel mechanism of action of NQO1 as RNA-binding protein may help to explain its pleiotropic biological effects.
2017-05-22 | GSE81614 | GEO
Project description:Background: Glioblastoma (GBM) is a highly aggressive brain tumor, with glioblastoma stem cells (GSCs) occupying the pinnacle of a complex tumor microenvironment (TME), conferring therapeutic resistance. The TME plays a role in tumor development by creating a niche rich in reactive oxygen species (ROS) through oxidative stress (OS). Here, we identified NAD(P)H quinone oxidoreductase-1 (NQO1) as an essential regulatory factor in antioxidant stress response, which is key to maintaining GSCs and the immunosuppressive TME. Methods: Proteomics analysis, epigenetic profile by using H3K27ac ChIP-sequencing and single-cell RNA sequencing were performed to define the high enrichment of NQO1 in GBM. In vitro and in vivo loss-of-function genetic and pharmacologic assays were conducted to evaluate the effect of NQO1 in GSC proliferation and self-renewal. Patient-derived GSCs and a xenograft murine model were using to investigate the tumor-intrinsic and extrinsic mechanisms to confers resistance to oxidative stress and reprogram the immunosuppressive TME. Results: NQO1 was preferentially expressed in GSCs and regulated ROS levels, preserving the stability of nuclear Lamin B1 and inhibiting cGAS-type I interferon signaling, which helps to remodel the immunosuppressive TME. Furthermore, nuclear factor erythroid 2-related factor 2 (NRF2) transcriptionally regulates NQO1, suppressing type I interferon signaling. Conclusions: NQO1 plays critical roles at both the cell-autonomous and cell-extrinsic levels for clinical treatment. Targeting NQO1 and its downstream signaling pathways, including β-Lapachone and immune checkpoint inhibitors such as anti-PD-1 therapy, enhances our understanding of the interactions between GSCs, oxidative stress, and the TME. This offers promising new avenues for clinical intervention in GBM.
2026-05-27 | GSE301343 | GEO
Project description:Aims: to evaluate the effects of site-specific phosphorylation (using phosphomimetic mutations at sites S40, S82 and T128) on multiple functional aspects of the antioxidant and disease-associated human flavoprotein NQO1. Results: in vitro biophysical studies revealed effects of phosphorylation at different sites such as decreased binding affinity for FAD and structural stability of its binding site (S82), conformational stability (S40 and S82) and reduced catalytic efficiency and functional cooperativity (T128). Local stability measurements by HDX in different ligation states provided insight into these effects. Transfection of eukaryotic cells showed that phosphorylation at sites S40 and S82 may reduce steady-levels of NQO1 protein by enhanced proteasome-induced degradation. Innovation: our approach allows to establish relationships between site-specific phosphorylation, functional and structural stability effects in vitro and inside cells paving the way for more detailed analyses of phosphorylation at the flavoproteome scale. Conclusions: we show that site-specific phosphorylation of human NQO1 may cause pleitropic and counterintuitive effects on this multifunctional protein with potential implications for its relationships with human disease.
2022-09-20 | PXD034600 | Pride