Browsing by Subject "Metabolic pathways"

Now showing 1 - 3 of 3
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    Lapachol inhibits glycolysis in cancer cells by targeting pyruvate kinase M2
    (Public Library of Science, 2018-02-02) Babu, Mani Shankar; Mahanta, Sailendra; Lakhter, Alexander J.; Hato, Takashi; Paul, Subhankar; Naidu, Samisubbu R.; Microbiology and Immunology, School of Medicine
    Reliance on aerobic glycolysis is one of the hallmarks of cancer. Although pyruvate kinase M2 (PKM2) is a key mediator of glycolysis in cancer cells, lack of selective agents that target PKM2 remains a challenge in exploiting metabolic pathways for cancer therapy. We report that unlike its structural analog shikonin, a known inhibitor of PKM2, lapachol failed to induce non-apoptotic cell death ferroxitosis in hypoxia. However, melanoma cells treated with lapachol showed a dose-dependent inhibition of glycolysis and a corresponding increase in oxygen consumption. Accordingly, in silico studies revealed a high affinity-binding pocket for lapachol on PKM2 structure. Lapachol inhibited PKM2 activity of purified enzyme as well as in melanoma cell extracts. Blockade of glycolysis by lapachol in melanoma cells led to decreased ATP levels and inhibition of cell proliferation. Furthermore, perturbation of glycolysis in melanoma cells with lapachol sensitized cells to mitochondrial protonophore and promoted apoptosis. These results present lapachol as an inhibitor of PKM2 to interrogate metabolic plasticity in tumor cells.
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    Pathway Enrichment of Longitudinal AD Endophenotypes Identifies Potential Therapeutic Targets for Modifying Disease Trajectory
    (Wiley, 2025-01-09) Jacobson Rosewood, Thea; Nho, Kwangsik; Risacher, Shannon L.; Liu, Shiwei; Gao, Sujuan; Saykin, Andrew J.; Radiology and Imaging Sciences, School of Medicine
    Background: Alzheimer’s disease (AD) is characterized by longitudinal changes of biomarker endophenotypes over the course of the disease prodrome, onset, and progression. The genetic pathways that influence these heterogenous changes in longitudinal endophenotype trajectories may provide insight into disease mechanisms and represent potential therapeutic targets. Methods: Longitudinal endophenotypes from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were selected: amyloid‐β (Amyloid PET and CSF), total tau and phosphorylated tau (CSF), glucose metabolism (FDG PET), neurodegeneration (atrophy on MRI), and cognition (composite scores for memory and executive functioning). Genome‐wide association analysis for the selected longitudinal endophenotypes was performed using Linear Mixed Modelling (LMM; LME4 R package), with (Time x Subject) as a random effect and age as the time variable. Gene‐based association analysis was performed using MAGMA on SNP P values from the LMM. The SNP to gene assignment was performed in two steps to select SNPs with a functional relation to each target gene: SNPs within gene transcription start and end positions, and SNPs that have significant eQTLs in brain tissue from the MetaBrain eQTL project. Gene‐based analysis results were then processed for gene‐set enrichment with MAGMA and the C2 curated gene set collection from the Gene Set Enrichment Analysis (GSEA) Molecular Signatures Database (MSigDB). Results: Pathway enrichment analysis identified 19 pathways (Figure 1) as significantly associated with longitudinal trajectories of AD endophenotypes. These pathways fall into six groups, with each pathway group having stronger association with different types of endophenotypes. Immune and cytoskeletal pathways largely associated with changes in amyloid trajectory. Metabolic pathways associated strongly with changes in amyloid and tau trajectories. Glycosylation pathways were associated with changes in brain atrophy. Pathways related to cell and neuronal signaling associated with changes in cognition, tau, and amyloid trajectories. Cell growth and survival was associated with changes in neurodegeneration trajectory (structural atrophy and hypometabolism). Conclusions: Pathway enrichment analysis of genetic variation associated with longitudinal changes of AD endophenotypes identified pathways that uniquely associate with trajectories of key AD biomarkers and cognition. These pathways may provide insight into AD pathological mechanisms and constitute new potential therapeutic targets to modify disease trajectory.
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    SIRT6 Promotes Hepatic Beta-Oxidation via Activation of PPARα
    (Elsevier, 2019-12-17) Naiman, Shoshana; Huynh, Frank K.; Gil, Reuven; Glick, Yair; Shahar, Yael; Touitou, Noga; Nahum, Liat; Avivi, Matan Y.; Roichman, Asael; Kanfi, Yariv; Gertler, Asaf A.; Doniger, Tirza; Ilkayeva, Olga R.; Abramovich, Ifat; Yaron, Orly; Lerrer, Batia; Gottlieb, Eyal; Harris, Robert A.; Gerber, Doron; Hirschey, Matthew D.; Cohen, Haim Y.; Biochemistry and Molecular Biology, School of Medicine
    The pro-longevity enzyme SIRT6 regulates various metabolic pathways. Gene expression analyses in SIRT6 heterozygotic mice identify significant decreases in PPARα signaling, known to regulate multiple metabolic pathways. SIRT6 binds PPARα and its response element within promoter regions and activates gene transcription. Sirt6+/− results in significantly reduced PPARα-induced β-oxidation and its metabolites and reduced alanine and lactate levels, while inducing pyruvate oxidation. Reciprocally, starved SIRT6 transgenic mice show increased pyruvate, acetylcarnitine, and glycerol levels and significantly induce β-oxidation genes in a PPARα-dependent manner. Furthermore, SIRT6 mediates PPARα inhibition of SREBP-dependent cholesterol and triglyceride synthesis. Mechanistically, SIRT6 binds PPARα coactivator NCOA2 and decreases liver NCOA2 K780 acetylation, which stimulates its activation of PPARα in a SIRT6-dependent manner. These coordinated SIRT6 activities lead to regulation of whole-body respiratory exchange ratio and liver fat content, revealing the interactions whereby SIRT6 synchronizes various metabolic pathways, and suggest a mechanism by which SIRT6 maintains healthy liver.