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Inhibition of HIF1α and PDK Induces Cell Death of Glioblastoma Multiforme
- Source :
- Experimental Neurobiology
- Publication Year :
- 2017
- Publisher :
- The Korean Society for Brain and Neural Science, 2017.
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Programmed cell death
Pyruvate dehydrogenase kinase
HIF1alpha
Oxidative phosphorylation
03 medical and health sciences
Cellular and Molecular Neuroscience
chemistry.chemical_compound
medicine
Chrysin
neoplasms
biology
hypoxia
Hypoxia (medical)
nervous system diseases
030104 developmental biology
chemistry
Cell culture
Anaerobic glycolysis
Cancer research
biology.protein
Original Article
GLUT1
Neurology (clinical)
medicine.symptom
Glioblastoma
Subjects
Details
- ISSN :
- 20938144 and 12262560
- Volume :
- 26
- Database :
- OpenAIRE
- Journal :
- Experimental Neurobiology
- Accession number :
- edsair.doi.dedup.....d87f654f68e93a2648c2a2598fa81afe