Refining the Role of Pyruvate Dehydrogenase Kinases in Glioblastoma Development

Abstract

Glioblastoma (GB) are the most frequent brain cancers. Aggressive growth and limited treatment options induce a median survival of 12–15 months. In addition to highly proliferative and invasive properties, GB cells show cancer-associated metabolic characteristics such as increased aerobic glycolysis. Pyruvate dehydrogenase (PDH) is a key enzyme complex at the crossroads between lactic fermentation and oxidative pathways, finely regulated by PDH kinases (PDHKs). PDHKs are often overexpressed in cancer cells to facilitate high glycolytic flux. We hypothesized that targeting PDHKs, by disturbing cancer metabolic homeostasis, would alter GB progression and render cells vulnerable to additional cancer treatment. Using patient databases, distinct expression patterns of PDHK1 and PDHK2 in GB tissues were obvious. To disturb protumoral glycolysis, we modulated PDH activity through the genetic or pharmacological inhibition of PDHK in patient-derived stem-like spheroids. Striking effects of PDHKs inhibition using dichloroacetate were observed in vitro on cell morphology and metabolism, resulting in increased intracellular ROS levels and decreased proliferation and invasion. In vivo findings confirmed a reduction in tumor size and better survival of mice implanted with PDHK1 and PDHK2 knockout cells. Adding a radiotherapeutic protocol further resulted in a reduction in tumor size and improved mouse survival in our model.

Metabolic reprogramming and signalling cross-talks in tumour–immune interaction: a system-level exploration

“…The occurrences of astrocyte-specific metabolic properties, such as ATP synthesis through OXPHOS, elevated glutamate uptake and diminished fatty acid oxidation (FAO), were observed in the model and found to be consistent with the astrocytic behaviour [30,36]. Glioma-specific metabolic properties, such as glycolysis leading to lactate formation and downregulation of PYDH, were also observed [37]. Furthermore, the model exhibited higher flux through glutamine uptake in glioma compared with astrocytes, enhanced release of glutamate through xCT, higher flux through arginase, downregulation of OXPHOS and enhanced FAO [38,39], which are the characteristic metabolic properties of glioma and serve to validate the glioma behaviour within the model (figure 2 a ).…”

A combined analysis of bulk and single-cell sequencing data reveals metabolic enzyme, pyruvate dehydrogenase E1 subunit beta (PDHB), as a prediction biomarker for the tumor immune response and immunotherapy

“…Pyruvate dehydrogenase E1 subunit beta (PDHB) is a major subunit of pyruvate dehydrogenase (PDH) [ 3 ]. PDH can catalyze the decarboxylation of pyruvate and participating in the glycolytic pathway, thereby regulating cellular energy metabolism [ 4 ]. As an important subunit of PDH, PDHB may favorably alter the reprogramming of tumor metabolism [ 5 ].…”

In-vivo magnetic resonance spectroscopy of lactate as a non-invasive biomarker of dichloroacetate activity in cancer and non-cancer central nervous system disorders

“…Because cytoplasmic pyruvate and lactate are in equilibrium, inhibition of PDC also results in intracellular accumulation of lactate. Upregulation of PDK and consequent elevation of lactate levels play a major role in the glycolytic reprogramming seen in the cancer microenvironment (2) that is associated with decreased apoptotic function (3), invasive phenotypes (4,5), decreased antitumor immunity (6) and shorter survival in animal models (7) and patients with various cancers (8,9).…”