Valproic acid suppresses Warburg effect and tumor progression in neuroblastoma.

Abstract

Altered glucose metabolism is a hallmark for cancer, which is characterized by a unique metabolic phenotype known as Warburg effect or aerobic glycolysis. Emerging studies show that valproic acid (VPA), an established histone deacetylase inhibitor, possesses tumor suppressive properties. However, the effects of VPA on the regulation of Warburg effect in neuroblastoma (NB), the most common extracranial malignancy in childhood, still remain elusive. In this study, we show that VPA inhibits the aerobic glycolysis in NB cells by decreasing glucose uptake and reducing lactate and ATP production. Mechanistically, VPA suppresses aerobic glycolysis via reducing the levels of E2F transcription factor 1 (E2F1), resulting in repressed expression of glycolytic genes glucose-6-phosphate isomerase (GPI) and phosphoglycerate pinase 1 (PGK1). Rescue experiments show that VPA inhibits the aerobic glycolysis and NB progression through down-regulation of E2F1. These results demonstrate that VPA suppresses the Warburg effect and tumor progression, indicating a novel therapeutic strategy for NB.

• Authors: Erhu Fang, Jianqun Wang, Mei Hong, Liduan Zheng, Qiangsong Tong
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 508 Issue 1 Pg. 9-16 (01 01 2019) ISSN: 1090-2104 [Electronic] United States
• PMID: 30466785 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Cytokines
• E2F1 Transcription Factor
• E2F1 protein, human
• Histone Deacetylase Inhibitors
• Valproic Acid
• PGK1 protein, human
• Phosphoglycerate Kinase
• GPI protein, human
• Glucose-6-Phosphate Isomerase

Topics

• Aerobiosis
• Animals
• Antineoplastic Agents (therapeutic use)
• Child
• Cytokines (genetics, metabolism)
• Disease Progression
• Down-Regulation (drug effects)
• E2F1 Transcription Factor (genetics, metabolism)
• Female
• Glucose-6-Phosphate Isomerase (genetics, metabolism)
• Glycolysis (drug effects)
• Histone Deacetylase Inhibitors (therapeutic use)
• Humans
• Mice
• Mice, Inbred C57BL
• Mice, Nude
• Neuroblastoma (drug therapy, metabolism, pathology)
• Phosphoglycerate Kinase (genetics, metabolism)
• Valproic Acid (therapeutic use)
• Xenograft Model Antitumor Assays