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

• Published in: FEBS open bio 2024-05, Vol.14 (5), p.843-854
• Main Authors: Pagano, Cristina, Coppola, Laura, Navarra, Giovanna, Avilia, Giorgio, Savarese, Beatrice, Torelli, Giovanni, Bruzzaniti, Sara, Piemonte, Erica, Galgani, Mario, Laezza, Chiara, Bifulco, Maurizio
• Format: Article
• Language: English
• Subjects: Acidification; Antibodies; Antineoplastic Agents - pharmacology; Antitumor agents; Apoptosis; Apoptosis - drug effects; Brain Cancer; Brain Neoplasms - drug therapy; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; cancer metabolism; Cancer therapies; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell culture; Cell cycle; Cell death; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Central nervous system; DNA methylation; Epidermal growth factor; Epidermal growth factor receptors; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; Glioblastoma cells; Glioma; Glioma cells; Glucose; Glycolysis; Glycolysis - drug effects; Humans; Informed consent; iPA; Isopentenyladenosine - metabolism; Isopentenyladenosine - pharmacology; Kinases; Lactic acid; Medical research; Membrane Proteins - genetics; Membrane Proteins - metabolism; Metabolic pathways; Metabolism; Mevalonate pathway; Necroptosis; Neurosurgery; NF-κB protein; PKM2; Proteins; Pyruvate kinase; Pyruvic acid; Respiration; Thyroid Hormone-Binding Proteins; Thyroid Hormones - metabolism; Tumors
• ISSN: 2211-5463; 2211-5463
• DOI: 10.1002/2211-5463.13766

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. The Warburg effect, also known as aerobic glycolysis, is characterized by high glucose uptake and lactate release even when sufficient oxygen is present. By reducing pyruvate kinase M2 (PKM2) via inhibition of the nuclear factor kappa B (NF‐κB) signaling pathway, N6‐isopentenyladenosine (iPA) decreases the Warburg effect in glioblastoma cells, thus impairing cancer cell proliferation.