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.