Protein kinase CK2-dependent aerobic glycolysis-induced lactate dehydrogenase A enhances the migration and invasion of cancer cells

Dae-Kyun Im,Jong Suk Lee,Heesun Cheong,Kyung Mi Yang,Min-Kyu Oh

doi:10.1038/s41598-019-41852-4

Abstract

We investigated the intracellular metabolic fluxes of protein kinase CK2-activating (Cα OE) cells and role of lactate dehydrogenase A (LDHA) as a contributor of tumorigenesis after reprogrammed glucose metabolism. Facilitated aerobic glycolysis was confirmed via isotope tracer analysis, in which 13C6-Glc or 13C5-Gln was added to the media, following which metabolites converted from Cα OE cells were identified. We found a greater decrease in cell survival, colony-forming ability, migration, and Cα OE cell invasion under glucose (Glc)-depletion conditions than under glutamine (Gln)-depletion conditions. Cancer cell migration and invasion increased due to LDHA elevation of the altered metabolic axis driven by activated CK2. FX11 treatment and LDHA knockdown suppressed migration and invasion through ROS generation, but this was partially reversed by the antioxidant N-acetylcysteine (NAC). Moreover, LDHA inhibition decreased tumor growth in a mouse xenograft model transplanted with Cα OE cells. Finally, we concluded that LDHA is an excellent metabolic target for tumor therapy, based on CK2α derived aerobic glycolysis.

Highlights

Cancer cell migration and invasion increased due to lactate dehydrogenase A (LDHA) elevation of the altered metabolic axis driven by activated CK2
Cancer cells fervently absorb Glc during aerobic metabolism, which is metabolized to pyruvate, followed by conversion preferably to lactate by lactate dehydrogenase A (LDHA), as opposed to entering the mitochondrial tricarboxylic acid (TCA) cycle[8]
To assess the nutritional requirements of Cα OE cells with regards to a carbon source, cell growth was observed under Glc- and Gln-depletion conditions

Summary

Introduction

Cancer cell migration and invasion increased due to LDHA elevation of the altered metabolic axis driven by activated CK2. We concluded that LDHA is an excellent metabolic target for tumor therapy, based on CK2α derived aerobic glycolysis. Glucose (Glc) and glutamine (Gln) support the biological hallmarks of malignancy[6,7] They are the main fuel for cancer cell growth and are used for biosynthesis and energy generation. It was reported that high LDHA expression in human lung carcinoma and hepatocellular carcinoma markedly increased the invasive potential and was associated with the generation of lactate[11,12]. Glycolysis and mitochondrial respiration are tightly coupled processes[15] They have been reported to facilitate the cancer stem cell phenotype, angiogenesis, migration, and immune evasion by influencing the cancer www.nature.com/scientificreports/

Methods

Results

Conclusion