Glioblastoma (GBM), the most common adult primary malignant brain tumor, carries a high morbidity and mortality despite therapeutic advances. GBM’s progression is associated with a transition from oxidative phosphorylation to aerobic glycolysis as its main source of energy. Our laboratory recently confirmed that overexpression of pyruvate dehydrogenase kinase isoform 1 (PDK1) positively contributes to GBM progression. Here we report a novel role of mitofusin 1 (MFN1), a mitochondrial outer membrane GTPase that is a key regulator of mitochondrial fusion associated with glycolysis. We have shown that both PDK1 and MFN1 are highly co-expressed in glioblastoma patient specimens. Data obtained from The Cancer Genome Atlas demonstrated a positive correlation between PDK1 and MFN1 mRNA levels and the survival of GBM patients. The data obtained from the subtyped glioma stem cells corroborated with the datamining studies. To directly explore the potential MFN1-PDK1 interplay, we used CRISPR/Cas9 to suppress MFN1 expression in proneural, classical and mesenchymal subtypes of GBM stem cells (CSC). In another experiment, using ChIP assay, we showed that both PDK1 and MFN1 are under the transcriptional control of Myc oncogene. We present evidence that silencing MFN1 regulates altered metabolism in GBM CSC by increasing ROS levels, altering mitochondrial membrane potential, reduced lactate metabolites via NMR spectroscopy. Taken together, our results indicate that combined targeting of PDK1 and MFN1 shift Warburg effect towards oxidative phosphorylation, and may have increased therapeutic potential for glioblastoma patients.

Citation Format: Maheedhara R. Guda, Swapna Asuthkar, Andrew J. Tsung, Kiran K. Velpula. PDK1 is a preferential metabolic target in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3593.