FDXR Drives Primary and Endocrine Resistant Tumor Cell Growth in ER+ Breast Cancer via CPT1A-Mediated Fatty Acid Oxidation
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ABSTRACT:
PROVIDER: PRJNA901367 | ENA |
REPOSITORIES: ENA
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Project description:The majority of breast cancers (BCs) harboring estrogen receptor (ER) have shown endocrine resistance. Our previous study has demonstrated that ferredoxin reductase (FDXR) promotes mitochondrial function and ER+ breast tumorigenesis. Here, integrative analyses of targeted metabolomics assay and gene expression profiling show that FDXR potentiates fatty acid oxidation (FAO) through positive regulation of carnitine palmitoyltransferase 1A (CPT1A) expression. Treatment with ER antagonist (tamoxifen) or degrader (fulvestrant) leads to increased expression of FDXR and CPT1A. In line with this finding, we find that FDXR-CPT1A-FAO axis is required for primary and endocrine resistant breast cancer cell growth. Therapeutically,combining endocrine therapy with FAO inhibitor synergistically reduces primary and endocrine resistant breast cancer cell growth, thus providing a potential combinatory treatment for ER+ breast cancer. We used microarrays to be able to elucidate to some extent the gene regulatory mechanisms of FDXR regulating breast cancer metabolism.
2023-05-24 | GSE217902 | GEO
Project description:Mitochondrial fatty acid oxidation is facilitated by the combined activities of Carnitine Palmitoyltransferase 1 and Carnitine Palmitoyltransferase 2 which generate and utilize acylcarnitines respectively. We compared the response of mice with liver specific deficiencies in the liver enriched Cpt1a or the ubiquitous Cpt2 and discovered that they display unique metabolic, physiological and molecular phenotypes. The loss of Cpt1a or Cpt2 resulted in the induction of the muscle enriched isoenzyme, Cpt1b, in hepatocytes in a Ppara dependent manner. Primary component analysis also revealed overall differential grouping between mouse with deletions of either Cpt1a or Cpt2. Our results utilize stringent genetic mouse models to elucidate that the sequential steps to facilitate mitochondrial fatty acid oxidation may have other factors.
2024-05-31 | GSE267915 | GEO
Project description:Metabolic reprogramming is a hallmark of tumorigenesis and includes alterations in glucose and fatty acid metabolism. In this study, we investigated the role of Carnitine palmitoyl transferase 1A (CPT1A), a key enzyme in fatty acid oxidation (FAO), in the induction of HER2+ (Human Epidermal growth factor 2, ErbB2) breast cancer. Using an ErbB2+ genetically engineered mouse models, we found that ablation of CPT1A delayed tumor onset and reduced tumor growth, angiogenesis, and metastatic capacity. CPT1A-deficient ErbB2+ cells exhibited impaired mitochondrial function, leading to a reliance on the tricarboxylic acid cycle to reduce NAD+/FAD for energy production. Consequently, loss of CPT1A resulted in glucose dependency and an inability to metabolize fats. CPT1A-deficient ErbB2+ tumor cells exhibited increased oxidative stress and upregulated nuclear factor erythroid 2-related factor 2 (NRF2) activity. Inhibiting NRF2 or silencing its expression reduced proliferation and glucose consumption in CPT1A-deficient cells. In pre-clinical models of ErbB2+ breast cancer, combining a ketogenic diet with an anti-ErbB2 monoclonal antibody in the context of CPT1A deficiency significantly reduced tumor growth and increased survival. Furthermore, combining the ketogenic diet with CPT1A ablation suppressed tumor growth, enhanced apoptosis, and reduced lung metastasis. Additionally, using an immunocompetent model, we provide evidence that CPT1A inhibition attenuated tumor growth and proliferation by promoting an antitumor immune microenvironment that enhanced the efficacy of ErbB2 targeted therapy. These findings provide insight into the metabolic rewiring in HER2+ breast cancer and highlight the potential of targeting fatty acid oxidation and employing metabolic interventions as a combination therapy strategy for HER2+ breast cancer patients, including those resistant to standard treatment regimes.
2024-07-08 | GSE254622 | GEO
Project description:Lymphatic vessels are involved in fluid drainage and are critical for health. To date, only genetic signaling pathways have been implicated in lymphatic development, and a role for metabolism has not been described. Here, we report that transcription factor Prox1 increases fatty acid ß-oxidation (FAO) through upregulation of CPT1a, a rate-controlling step of FAO. Lymphatic endothelial cells (LECs) oxidize fatty acids to proliferate and migrate. By providing acetyl-CoA, FAO is also critical for the maintenance of differentiated LECs through the regulation of histone acetylation of key lymphangiogenic genes. Loss of CPT1a in LEC precursors causes lymphatic defects in vivo, while restoration of acetyl-CoA by supplementing acetate to replenish cellular acetyl-CoA levels rescues this process.
2017-02-13 | GSE71230 | GEO
Project description:Carnitine palmitoyltransferase 1a (CPT1a) is the key regulator of mitochondrial long-chain fatty acid beta-oxidation (LCFAO). However, the functional significance of AT2 cell-specific LCFAO at baseline and during acute lung injury (ALI) is not fully understood. In this study, Murine models of AT2 cell-specific Cpt1a deletion were generated for investigating the role of CPT1a in regulating AT2 cell function and the severity of lipopolysaccharide-induced murine ALI models.
2024-07-05 | GSE224354 | GEO
Project description:We performed a label-free quantitative proteomic profiling to determine the effect of Polygonum perfoliatum L. treated the proteomics profile of liver tissue and identified activated PPARs/CPT1A/CPT2-mediated hepatic fatty acid β oxidation process was significantly altered
2024-02-05 | PXD033219 |
Project description:Little is known about metabolic changes accompanying endothelial cell (EC) quiescence. Nonetheless, when dysfunctional, quiescent ECs (QECs) contribute to multiple cardiovascular diseases. ECs need fatty acid β-oxidation (FAO) for proliferation. Surprisingly, we now report that QECs are not hypo-metabolic, but upregulate FAO >3-fold higher than proliferating ECs (PECs), not to support biomass or energy production, but to sustain the TCA cycle for redox homeostasis through NADPH production. Hence, inhibition of FAO-controlling CPT1A promotes EC dysfunction (anti-fibrinolysis, leukocyte infiltration, barrier disruption) by increasing oxidative stress in CPT1AΔEC mice with endothelial CPT1A loss. Mechanistically, Notch1 orchestrates the use of FAO for redox balance in QECs. Supplementation of acetate (metabolized to acetyl-CoA) induces vasculoprotection against oxidative stress and EC dysfunction in CPT1AΔEC mice, possibly creating therapeutic opportunities. Thus, ECs use FAO for vasculoprotection against their high oxygen (oxidative stress-prone) milieu, and for different metabolic purposes dependent on their proliferation versus quiescence status.
2018-09-12 | E-MTAB-6595 | biostudies-arrayexpress
Project description:Mitochondrial fatty acid oxidation is facilitated by the combined activities of Carnitine Palmitoyltransferase 1 and Carnitine Palmitoyltransferase 2 which generate and utilize acylcarnitines respectively. We compared the response of mice with liver specific deficiencies in Cpt1a and Cpt1b, Cpt2, or the triple deletion of all three acyltransferases. We discovered that they display unique metabolic, physiological and molecular phenotypes. The loss of Cpt1a and Cpt1b or Cpt2 resulted in particular transcriptional outputs in hepatocytes. We show that much of the transcriptional signature is suppressed when deleting both Cpt2 and Ppara, showing the contribution of Ppara. Our results utilize stringent genetic mouse models to characterize the differential phenotypes of mice lacking Cpt1a and Cpt1b or Cpt2 and also show the contribution of a major transcription factor, Ppara.
2024-05-31 | GSE267916 | GEO
Project description:Carnitine palmitoyltransferase 1a (CPT1a) is the key regulator of mitochondrial long-chain fatty acid beta-oxidation (LCFAO). However, the functional significance of AT2 cell-specific LCFAO at baseline and during acute lung injury (ALI) is not fully understood. In this study, Murine models of AT2 cell-specific Cpt1a deletion were generated for investigating the role of CPT1a in regulating AT2 cell function and the severity of lipopolysaccharide-induced murine ALI models.
2024-07-05 | GSE255949 | GEO
Project description:Hepatosteatosis, defined as excessive intrahepatic lipid accumulation, represents the first step in the development of NAFLD. However, the molecular events directly caused by hepatic lipid build-up, in terms of its impact on liver biology and other peripheral organs, remain unclear. Carnitine palmitoyltransferase 1A (CPT1A) is the rate limiting enzyme for long chain fatty acid beta-oxidation in the liver. Here we utilise hepatocyte-specific Cpt1a knockout (LKO) mice to investigate the physiological consequences of abolishing hepatic long chain fatty acid metabolism to NAFLD and systemic metabolic homeostasis. We show that LKO mice displayed more severe hepatosteatosis but were otherwise protected against diet-induced weight gain, insulin resistance, hepatic ER stress and damage in response to high fat diets. Furthermore, increased energy expenditure accompanied by enhanced adipose tissue browning was observed in LKO mice. Mechanistically, hepatic CPT1A deficiency actives the peroxisome proliferator activator alpha (PPARα)- fibroblast growth factor 21 (FGF21) axis and the elevation of FGF21 contributes to the improved liver pathology and adipose browning in HFD-treated LKO mice. Thus, our study demonstrates that liver with deficient CPT1A expression adopts a healthy steatotic status that protects against HFD-evoked liver damage and potentiates adipose browning in an FGF21-dependent manner. Inhibition of hepatic CPT1A may serve as a viable strategy for the treatment of obesity and NAFLD.
2022-09-10 | GSE183650 | GEO