Comprehensive Analysis of Glycolytic Enzymes as Therapeutic Targets in the Treatment of Glioblastoma

Abstract

Major efforts have been put in anti-angiogenic treatment for glioblastoma (GBM), an aggressive and highly vascularized brain tumor with dismal prognosis. However clinical outcome with anti-angiogenic agents has been disappointing and tumors quickly develop escape mechanisms. In preclinical GBM models we have recently shown that bevacizumab, a blocking antibody against vascular endothelial growth factor, induces hypoxia in treated tumors, which is accompanied by increased glycolytic activity and tumor invasiveness. Genome-wide transcriptomic analysis of patient derived GBM cells including stem cell lines revealed a strong up-regulation of glycolysis-related genes in response to severe hypoxia. We therefore investigated the importance of glycolytic enzymes in GBM adaptation and survival under hypoxia, both in vitro and in vivo. We found that shRNA-mediated attenuation of glycolytic enzyme expression interfered with GBM growth under normoxic and hypoxic conditions in all cellular models. Using intracranial GBM xenografts we identified seven glycolytic genes whose knockdown led to a dramatic survival benefit in mice. The most drastic effect was observed for PFKP (PFK1, +21.8%) and PDK1 (+20.9%), followed by PGAM1 and ENO1 (+14.5% each), HK2 (+11.8%), ALDOA (+10.9%) and ENO2 (+7.2%). The increase in mouse survival after genetic interference was confirmed using chemical inhibition of PFK1 with clotrimazole. We thus provide a comprehensive analysis on the importance of the glycolytic pathway for GBM growth in vivo and propose PFK1 and PDK1 as the most promising therapeutic targets to address the metabolic escape mechanisms of GBM.

Targeted knockdown of polo-like kinase 1 alters metabolic regulation in melanoma

“…In renal cell carcinoma, ENO2 was not found to affect tumor growth [24]. However, another recent study has shown a correlation in glioblastomas between increased ENO2 expression and tumor progression in vivo [25]. Further studies will be required to determine the role of ENO2 in melanoma.…”

Reactive oxygen species (ROS) are a key determinant of cancer's metabolic phenotype

“…A glycolytic metabolism is highly correlated with tumor proliferation. Knockdown or pharmacological inhibition of glycolytic enzymes reduces growth in a variety of cancers . Forced induction of respiration has led to slower growth rates both in vitro and in vivo .…”

“…Knockdown or pharmacological inhibition of glycolytic enzymes reduces growth in a variety of cancers. [50][51][52][53] Forced induction of respiration has led to slower growth rates both in vitro and in vivo. 6,54,55 Conversely, lower oxidative phosphorylation due to mutant mitochondria increases both glycolysis and growth.…”

A new potential anti‐cancer beta‐carboline derivative decreases the expression levels of key proteins involved in glioma aggressiveness: A proteomic investigation

“…PGAM1 is an enzyme participating in glycolysis by converting 3‐PG (3‐phosphoglycerate) to 2‐PG (Fothergill‐Gilmore & Watson, ) whose expression also correlates with glioma grade and patient survival (Gao et al, ). Although its role in cancer is still poorly understood, its knockdown increases the survival of glioblastoma bearing mice (Sanzey et al, ). PGAM1 downregulation appeared thus as an interesting possible event triggered by CM16 to combat glioma.…”