MiR-128-3p contributes to mitochondrial dysfunction and induces apoptosis in glioma cells via targeting pyruvate dehydrogenase kinase 1.

Abstract

Glioma, like most cancers, possesses a unique bioenergetic state of aerobic glycolysis known as the Warburg effect, which is a dominant phenotype of most tumor cells. Glioma tumors exhibit high glycolytic metabolism with increased lactate production. Data derived from the gene expression profiling interactive analysis (GEPIA) database show that pyruvate dehydrogenase kinase 1 (PDK1) is significantly highly expressed in glioma tissues compared with corresponding normal tissues. PDK1 is a key enzyme in the transition of glycolysis to tricarboxylic acid cycle, via inactivating PDH and converting oxidative phosphorylation to Warburg effect, resulting in increment of lactate production. Silencing of PDK1 expression resulted in reduced lactate and ATP, accumulation of ROS, mitochondrial damage, decreased cell growth, and increased cell apoptosis. Aberrant expression of miR-128 has been observed in many human malignancies. Mechanistically, we discover that overexpressed miR-128-3p disturbs the Warburg effect in glioma cells via reducing PDK1. Our experiments confirmed that the miR-128-3p/PDK1 axis played a pivotal role in cancer cell metabolism and growth. Collectively, these findings suggest that therapeutic strategies to modulate the Warburg effect, such as targeting of PDK1, might act as a potential therapeutic target for glioma treatment.