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Targeting Fatty Acid Oxidation Enhances Response to HER2-targeted Therapy

ABSTRACT: Targeting Fatty Acid Oxidation Enhances Response to HER2-targeted Therapy

PROVIDER: PRJNA1071151 | ENA |

REPOSITORIES: ENA

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Targeting Fatty Acid Oxidation Enhances Response to HER2-targeted Therapy

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

Neonatal Intake of Omega-3 Fatty Acids Enhances Lipid Oxidation in Adipocyte Precursors

Project description:Neonatal Intake of Omega-3 Fatty Acids Enhances Lipid Oxidation in Adipocyte Precursors

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DNA damage-activated mitochondrial fatty acid oxidation drives senescence

Project description:Cellular senescence is a stress-induced irreversible cell cycle arrest involved in tumor suppression and aging. Many stresses, such as telomere shortening and oncogene activation, induce senescence by damaging nuclear DNA. However, the mechanisms linking DNA damage to senescence remain unclear. Here, we show that DNA damage response (DDR) signaling to mitochondria triggers senescence. A genome-wide siRNA screen implicated the outer mitochondrial transmembrane protein BNIP3 in senescence induction. We found that BNIP3 is a substrate of the DDR kinase ATM and contributes to an increase in the number of mitochondrial cristae upon DNA damage. Stable isotope labeling metabolomics indicated that this increase in cristae enhances the oxidation of fatty acids to acetyl-CoA. Notably, pharmacological activation of fatty acid oxidation alone induced senescence both in vitro and in vivo. Our findings suggest that mitochondrial energy metabolism plays a critical role in senescence induction and is a potential intervention target to control senescence.

2024-10-30 | GSE272659 | GEO

Repair of airway epithelia requires metabolic rewiring towards fatty acid oxidation

Project description:Repair of airway epithelia requires metabolic rewiring towards fatty acid oxidation

2023-01-31 | GSE218663 | GEO

Reduced fatty acid synthesis and enhanced oxidation promote human definitive endoderm differentiation

Project description:Metabolic remodeling is one of the earliest events that occur during the early differentiation of embryonic stem cells (ESCs), but how these metabolic changes are regulated and participate in the cell differentiation is still largely undissected. Here, we define the fatty acid metabolism as a key player in definitive endoderm (DE) differentiation from human ESCs. During DE differentiation, lipogenesis is decreased while fatty acid β oxidation is enhanced. This dynamic is due to the phosphorylation of lipogenic enzyme acetyl-CoA carboxylase (ACC), which is mediated by AMP-activated protein kinase (AMPK) and inhibits the de novo fatty acid synthesis. More importantly, inhibition of fatty acid synthesis by either its inhibitors or AMPK agonist, significantly promotes the human endoderm differentiation, while blockade of the fatty acid oxidation by genetic manipulation or chemical antagonists impairs the differentiation. The de novo fatty acid synthesis inhibition and fatty acid β oxidation maintaining contribute to the accumulation of cellular acetyl-CoA, which is the essential substrate for protein acetylation. Further study reveals that SMAD3 acetylation and the subsequent subcellular localization exhibit significant change upon interfering fatty acid metabolism. Mechanistically, the accumulation of cellular acetyl-CoA guarantees the acetylation of key transcription factor SMAD3, which further causes the nuclear localization and activation of SMAD signaling pathway to promote DE differentiation. Thus, our current study reveals a fatty acid synthesis/oxidation shift during early differentiation and presents an instructive role of fatty acid metabolism in regulating human early endoderm differentiation.

2023-07-02 | GSE218319 | GEO

Yap regulates fatty acid oxidation in skeletal muscle

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High-fat diet activated fatty acid oxidation mediates intestinal stemness and tumorigenicity

Project description:We apply scRNA-seq to identify shared patterns of gene expression related to fatty acid oxidation, across stem cells from the proximal small intestine, distal small intestine, and colon

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Rao2014 - Fatty acid beta-oxidation (reduced model)

Project description:This represents the reduced version of the "time course model" of Van Eunen et al (2013): Biochemical competition makes fatty-acid beta-oxidation vulnerable to substrate overload. The SBML was created from that of the original model and produces identical results when a time-course of 25 mins is run in COPASI

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Disruption of Estrogen Signaling Enhances Invasiveness of Breast Cancer Cells by Attenuating a HER2-independent Gene Repression Program

Project description:Disruption of Estrogen Signaling Enhances Invasiveness of Breast Cancer Cells by Attenuating a HER2-independent Gene Repression Program

2016-11-01 | GSE53734 | GEO

DNA damage-activated mitochondrial fatty acid oxidation drives senescence

Project description:DNA damage-activated mitochondrial fatty acid oxidation drives senescence

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