title: Combined targeting of PDK1 and EGFR triggers regression of glioblastoma by reversing the Warburg effect.
abstract: Glioblastoma multiforme is the most aggressive primary brain tumor in adults. Overexpression of the EGF receptor (EGFR) is recognized as a widespread oncogenic signature in glioblastoma multiforme, but the complexity of its contributions is not fully understood, nor the most effective ways to leverage anti-EGFR therapy in this setting. Hypoxia is known to drive the aggressive character of glioblastoma multiforme by promoting aerobic glycolysis rather than pyruvate oxidation carried out in mitochondria (OXPHOS), a phenomenon termed the Warburg effect, which is a general feature of oncogenesis. In this study, we report that hypoxia drives expression of the pyruvate dehydrogenase kinase (PDK1) and EGFR along with the hypoxia-inducing factor (HIF)-1α in human glioblastoma multiforme cells. PDK1 is a HIF-1-regulated gene and our findings indicated that hypoxia-induced PDK1 expression may promote EGFR activation, initiating a feed-forward loop that can sustain malignant progression. RNAi-mediated attenuation of PDK1 and EGFR lowered PDK1-EGFR activation and decreased HIF-1α expression, shifting the Warburg phenotype to OXPHOS and inhibiting glioblastoma multiforme growth and proliferation. In clinical specimens of glioblastoma multiforme, we found that immunohistochemical expression of PDK1, EGFR, and HIF-1α were elevated in glioblastoma multiforme specimens when compared with normal brain tissues. Collectively, our studies establish PDK1 as a key driver and candidate therapeutic target in glioblastoma multiforme.
authors.affiliation: Authors' Affiliations: Departments of Cancer Biology and Pharmacology, and Neurosurgery, University of Illinois College of Medicine at Peoria; and Illinois Neurological Institute, Peoria, Illinois.
authors.forename: Kiran Kumar
authors.initials: KK
authors.lastname: Velpula
authors.forename: Arnima
authors.initials: A
authors.lastname: Bhasin
authors.forename: Swapna
authors.initials: S
authors.lastname: Asuthkar
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Tsung
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D003999:Dichloroacetic Acid / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015398:Signal Transduction
chemical_list: C000631429:PDK1 protein, human; C000631433:Pdk1 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D003999:Dichloroacetic Acid; C512478:EGFR protein, human; D066246:ErbB Receptors; D017346:Protein Serine-Threonine Kinases