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Refining the Role of Pyruvate Dehydrogenase Kinases in Glioblastoma Development. | LitMetric

AI Article Synopsis

  • Glioblastoma (GB) is a highly aggressive brain cancer with a poor median survival rate of 12-15 months, largely due to its rapid growth and limited treatment options.
  • The study focuses on pyruvate dehydrogenase (PDH) kinases (PDHKs), which are often overexpressed in GB cells, contributing to their high glycolytic activity that supports tumor growth.
  • Targeting PDHKs through genetic or pharmacological methods, such as using dichloroacetate, significantly inhibited GB cells' proliferation and invasion, reduced tumor size, and improved survival rates in mouse models, especially when combined with radiotherapy.

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9367285PMC
http://dx.doi.org/10.3390/cancers14153769DOI Listing

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