Targeting metabolic remodeling in glioblastoma multiforme

Abstract

A key aberrant biological difference between tumor cells and normal differentiated cells is altered metabolism, whereby cancer cells acquire a number of stable genetic and epigenetic alterations to retain proliferation, survive under unfavorable microenvironments and invade into surrounding tissues. A classic biochemical adaptation is the metabolic shift to aerobic glycolysis rather than mitochondrial oxidative phosphorylation, regardless of oxygen availability, a phenomenon termed the "Warburg Effect". Aerobic glycolysis, characterized by high glucose uptake, low oxygen consumption and elevated production of lactate, is associated with a survival advantage as well as the generation of substrates such as fatty acids, amino acids and nucleotides necessary in rapidly proliferating cells. This review discusses the role of key metabolic enzymes and their association with aerobic glycolysis in Glioblastoma Multiforme (GBM), an aggressive, highly glycolytic and deadly brain tumor. Targeting key metabolic enzymes involved in modulating the "Warburg Effect" may provide a novel therapeutic approach either singularly or in combination with existing therapies in GBMs.

Keywords: cancer; drug discovery; oncotarget; stem cells; wnt.

Figure 1. Schematic of Metabolic Remodeling in GBM

Enzymes of glycolysis, the pentose phosphate pathway, fatty acid and glutamine metabolism and their regulation by known oncogenes and tumor suppressor genes in proliferating cells. Growth factor/PI3K/AKT signaling stimulates glucose uptake and flux through the early part of glycolysis. Tyrosine kinase signaling negatively regulates flux through at PKM2, making glycolytic intermediates available for macromolecular synthesis. Myc has been found to promote glutamine metabolism and inhibit oxidative metabolism by activating PDK. p53 decreases metabolic flux through glycolysis in response to cell stress.