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Browsing by Subject "Metabolic pathways"
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Item 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 MedicineReliance 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.Item 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 MedicineThe 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.