title: Cancer stem cell molecular reprogramming of the Warburg effect in glioblastomas: a new target gleaned from an old concept.
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.
authors.affiliation: Departments of Cancer Biology & Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL 61605, USA.
authors.forename: Carlen A
authors.initials: CA
authors.lastname: Yuen
authors.affiliation: Departments of Cancer Biology & Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL 61605, USA.
authors.forename: Swapna
authors.initials: S
authors.lastname: Asuthkar
authors.affiliation: Departments of Cancer Biology & Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL 61605, USA.
authors.forename: Maheedhara R
authors.initials: MR
authors.lastname: Guda
authors.affiliation: Departments of Cancer Biology & Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL 61605, USA.|Department of Neurosurgery, University of Illinois College of Medicine, Peoria, IL 61605, USA.|Illinois Neurological Institute, Peoria, IL 61605, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Tsung
authors.affiliation: Departments of Cancer Biology & Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL 61605, USA.|Department of Neurosurgery, University of Illinois College of Medicine, Peoria, IL 61605, USA.
authors.forename: Kiran K
authors.initials: KK
authors.lastname: Velpula
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D015687:Cell Hypoxia; D000066673:Cell Self Renewal; D065150:Cellular Reprogramming; D003999:Dichloroacetic Acid / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism*; D006019:Glycolysis; D006801:Humans; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D020533:Angiogenesis Inhibitors; D051792:Basic Helix-Loop-Helix Proteins; D003999:Dichloroacetic Acid; D009363:Neoplasm Proteins
keywords: GLUT1; HK2; LDHA; PDK1; PKM2; Warburg effect; hypoxia