Cancer stem cell molecular reprogramming of the Warburg effect in glioblastomas: a new target gleaned from an old concept

Author:

Yuen Carlen A1,Asuthkar Swapna1,Guda Maheedhara R1,Tsung Andrew J123,Velpula Kiran K12

Affiliation:

1. Departments of Cancer Biology & Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL 61605, USA

2. Department of Neurosurgery, University of Illinois College of Medicine, Peoria, IL 61605, USA

3. Illinois Neurological Institute, Peoria, IL 61605, USA

Abstract

Prior targeted treatment for glioblastoma multiforme (GBM) with anti-angiogenic agents, such as bevacizumab, has been met with limited success potentially owing to GBM tumor's ability to develop a hypoxia-induced escape mechanism – a glycolytic switch from oxidative phosphorylation to glycolysis, an old concept known as the Warburg effect. New studies points to a subpopulation of cells as a source for treatment-resistance, cancer stem cells (CSCs). Taken together, the induction of the Warburg effect leads to the promotion of CSC self-renewal and undifferentiation. In response to hypoxia, hypoxia-inducible transcription factor is upregulated and is the central driver in setting off the cascade of events in CSC metabolic reprogramming. Hypoxia-inducible transcription factor upregulates GLUT1 to increase glucose uptake into the cell, upregulates HK2 and PK during glycolysis, upregulates LDHA in the termination of glycolysis, and downregulates PDH to redirect energy production toward glycolysis. This review aims to unite these old and new concepts simultaneously and examine potential enzyme targets driven by hypoxia in the glycolytic phenotype of CSCs to reverse the metabolic shift induced by the Warburg effect.

Publisher

Future Medicine Ltd

Subject

General Medicine

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