• KSBNS 2024


Original Article

Exp Neurobiol 2017; 26(5): 295-306

Published online October 31, 2017

© The Korean Society for Brain and Neural Sciences

Inhibition of HIF1α and PDK Induces Cell Death of Glioblastoma Multiforme

Jiwon Esther Han1, Pyung Won Lim1, Chul Min Na1, You Sik Choi1, Joo Young Lee1, Yona Kim1, Hyung Woo Park1, Hyo Eun Moon1, Man Seung Heo2, Hye Ran Park1, Dong Gyu Kim1 and Sun Ha Paek1,3,4*

1Department of Neurosurgery, Seoul National University College of Medicine, Seoul 03082, 2Smart Healthcare Medical Device Research Center, Samsung Medical Center, Seoul 06351, 3Cancer Research Institute, Seoul National University College of Medicine, Seoul 03082, 4Hypoxia Ischemia Disease Institute, Seoul National University College of Medicine, Seoul 03082, Korea

Correspondence to: *To whom correspondence should be addressed.
TEL: 82-2-744-8459, FAX: 82-2-2072-3993

Received: August 30, 2017; Revised: October 7, 2017; Accepted: October 12, 2017


Glioblastoma multiforme (GBM) is the most common and aggressive form of brain tumors. GBMs, like other tumors, rely relatively less on mitochondrial oxidative phosphorylation (OXPHOS) and utilize more aerobic glycolysis, and this metabolic shift becomes augmented under hypoxia. In the present study, we investigated the physiological significance of altered glucose metabolism and hypoxic adaptation in the GBM cell line U251 and two newly established primary GBMs (GBM28 and GBM37). We found that these three GBMs exhibited differential growth rates under hypoxia compared to those under normoxia. Under normoxia, the basal expressions of HIF1α and the glycolysis-associated genes, PDK1, PDK3, and GLUT1, were relatively low in U251 and GBM28, while their basal expressions were high in GBM37. Under hypoxia, the expressions of these genes were enhanced further in all three GBMs. Treatment with dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), induced cell death in GBM28 and GBM37 maintained under normoxia, whereas DCA effects disappeared under hypoxia, suggesting that hypoxic adaptation dominated DCA effects in these GBMs. In contrast, the inhibition of HIF1α with chrysin suppressed the expression of PDK1, PDK3, and GLUT1 and markedly promoted cell death of all GBMs under both normoxia and hypoxia. Interestingly, however, GBMs treated with chrysin under hypoxia still sustained higher viability than those under normoxia, and chrysin and DCA co-treatment was unable to eliminate this hypoxia-dependent resistance. Together, these results suggest that hypoxic adaptation is critical for maintaining viability of GBMs, and targeting hypoxic adaptation can be an important treatment option for GBMs.

Keywords: Glioblastoma, HIF1alpha, hypoxia