Refining the Role of Pyruvate Dehydrogenase Kinases in Glioblastoma Development

SIMPLE SUMMARY: Finding new treatment strategies is an urgent need in cancer medicine, especially for the fast-growing and aggressive primary brain tumor glioblastoma (GB). Patients with GB face a median survival of about 15 months, despite tumor resection and radio-chemotherapy. In this study, we targeted cancer cell metabolism, specifically the pyruvate dehydrogenase (PDH) regulators PDH kinases (PDHK), to disturb GB progression. Indeed, PDHK1 and PDHK2 were found to be highly expressed in GB tissue cohorts and presented different expression patterns in distinct areas of the tumor. We used patient-derived stem-like cells to knockout PDHK1 or PDHK2, and dichloroacetate (DCA) to inhibit all PDHK activity. DCA showed massive in vitro effects on proliferation and invasion but no in vivo benefit as monotherapy when injected into GB-bearing mice. Finally, mice implanted with PDHK KO cells presented a higher survival rate than the control group; this effect was enhanced by performing cranial irradiation. 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.