N6-isopentenyladenosine inhibits aerobic glycolysis in glioblastoma cells by targeting PKM2 expression and activity.

Autor: Pagano C; Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', Naples, Italy., Coppola L; Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', Naples, Italy., Navarra G; Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', Naples, Italy., Avilia G; Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', Naples, Italy., Savarese B; Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', Naples, Italy., Torelli G; Neurosurgery Unit A.O. San Giovanni di Dio e Ruggi d' Aragona - Salerno's School of Medicine Largo Città di Ippocrate, Salerno, Italy., Bruzzaniti S; Institute of Endocrinology and Experimental Oncology (IEOS), National Research Council (CNR), Naples, Italy., Piemonte E; Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', Naples, Italy., Galgani M; Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', Naples, Italy., Laezza C; Institute of Endocrinology and Experimental Oncology (IEOS), National Research Council (CNR), Naples, Italy., Bifulco M; Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', Naples, Italy.
Jazyk: angličtina
Zdroj: FEBS open bio [FEBS Open Bio] 2024 May; Vol. 14 (5), pp. 843-854. Date of Electronic Publication: 2024 Mar 21.
DOI: 10.1002/2211-5463.13766
Abstrakt: Glioblastoma (GBM) is a primary tumor in the central nervous system with poor prognosis. It exhibits elevated glucose uptake and lactate production. This metabolic state of aerobic glycolysis is known as the Warburg effect. N6-isopentenyladenosine (iPA), a natural cytokine modified with an isopentenyl moiety derived from the mevalonate pathway, has well-established anti-tumor activity. It inhibits cell proliferation in glioma cells, inducing cell death by apoptosis and/or necroptosis. In the present study, we found that iPA inhibits aerobic glycolysis in unmodified U87MG cells and in the same cell line engineered to over-express wild-type epidermal growth factor receptor (EGFR) or EGFR variant III (vIII), as well as in a primary GBM4 patient-derived cell line. The detection of glycolysis showed that iPA treatment suppressed ATP and lactate production. We also evaluated the response of iPA treatment in normal human astrocyte primary cells, healthy counterpart cells of the brain. Aerobic glycolysis in treated normal human astrocyte cells did not show significant changes compared to GBM cells. To determine the mechanism of iPA action on aerobic glycolysis, we investigated the expression of certain enzymes involved in this metabolic pathway. We observed that iPA reduced the expression of pyruvate kinase M2 (PKM2), which plays a key role in the regulation of aerobic glycolysis, promoting tumor cell proliferation. The reduction of PKM2 expression is a result of the inhibition of the inhibitor of nuclear factor kappa-B kinase subunit, beta/nuclear factor-kappa B pathway upon iPA treatment. In conclusion, these experimental results show that iPA may inhibit aerobic glycolysis of GBM in stabilized cell lines and primary GBM cells by targeting the expression and activity of PKM2.
(© 2024 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
Databáze: MEDLINE
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