title: GLUT3 upregulation promotes metabolic reprogramming associated with antiangiogenic therapy resistance.
abstract: Clinical trials revealed limited response duration of glioblastomas to VEGF-neutralizing antibody bevacizumab. Thriving in the devascularized microenvironment occurring after antiangiogenic therapy requires tumor cell adaptation to decreased glucose, with 50% less glucose identified in bevacizumab-treated xenografts. Compared with bevacizumab-responsive xenograft cells, resistant cells exhibited increased glucose uptake, glycolysis,13C NMR pyruvate to lactate conversion, and survival in low glucose. Glucose transporter 3 (GLUT3) was upregulated in bevacizumab-resistant versus sensitive xenografts and patient specimens in a HIF-1α-dependent manner. Resistant versus sensitive cell mitochondria in oxidative phosphorylation-selective conditions produced less ATP. Despite unchanged mitochondrial numbers, normoxic resistant cells had lower mitochondrial membrane potential than sensitive cells, confirming poorer mitochondrial health, but avoided the mitochondrial dysfunction of hypoxic sensitive cells. Thin-layer chromatography revealed increased triglycerides in bevacizumab-resistant versus sensitive xenografts, a change driven by mitochondrial stress. A glycogen synthase kinase-3β inhibitor suppressing GLUT3 transcription caused greater cell death in bevacizumab-resistant than -responsive cells. Overexpressing GLUT3 in tumor cells recapitulated bevacizumab-resistant cell features: survival and proliferation in low glucose, increased glycolysis, impaired oxidative phosphorylation, and rapid in vivo proliferation only slowed by bevacizumab to that of untreated bevacizumab-responsive tumors. Targeting GLUT3 or the increased glycolysis reliance in resistant tumors could unlock the potential of antiangiogenic treatments.
authors.affiliation: Department of Neurological Surgery.
authors.forename: Ruby
authors.initials: R
authors.lastname: Kuang
authors.affiliation: Department of Neurological Surgery.
authors.forename: Arman
authors.initials: A
authors.lastname: Jahangiri
authors.affiliation: Department of Neurological Surgery.
authors.forename: Smita
authors.initials: S
authors.lastname: Mascharak
authors.affiliation: Department of Neurological Surgery.
authors.forename: Alan
authors.initials: A
authors.lastname: Nguyen
authors.affiliation: Department of Neurological Surgery.
authors.forename: Ankush
authors.initials: A
authors.lastname: Chandra
authors.affiliation: Department of Neurological Surgery.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Flanigan
authors.affiliation: Department of Neurological Surgery.
authors.forename: Garima
authors.initials: G
authors.lastname: Yagnik
authors.affiliation: Department of Neurological Surgery.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Wagner
authors.affiliation: Department of Neurological Surgery.
authors.forename: Michael
authors.initials: M
authors.lastname: De Lay
authors.affiliation: Department of Neurological Surgery.
authors.forename: Diego
authors.initials: D
authors.lastname: Carrera
authors.affiliation: Department of Neurological Surgery.
authors.forename: Brandyn A
authors.initials: BA
authors.lastname: Castro
authors.affiliation: Department of Neurological Surgery.
authors.forename: Josie
authors.initials: J
authors.lastname: Hayes
authors.affiliation: Department of Neurological Surgery.
authors.forename: Maxim
authors.initials: M
authors.lastname: Sidorov
authors.affiliation: Department of Radiology.
authors.forename: Jose Luiz Izquierdo
authors.initials: JLI
authors.lastname: Garcia
authors.affiliation: Department of Radiology.
authors.forename: Pia
authors.initials: P
authors.lastname: Eriksson
authors.affiliation: Department of Radiology.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Ronen
authors.affiliation: Department of Neuropathology, and.
authors.forename: Joanna
authors.initials: J
authors.lastname: Phillips
authors.affiliation: Department of Neurological Surgery.
authors.forename: Annette
authors.initials: A
authors.lastname: Molinaro
authors.affiliation: Diabetes Center, University of California at San Francisco, San Francisco, California, USA.
authors.forename: Suneil
authors.initials: S
authors.lastname: Koliwad
authors.affiliation: Department of Neurological Surgery.
authors.forename: Manish K
authors.initials: MK
authors.lastname: Aghi
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000068258:Bevacizumab / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D005909:Glioblastoma / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D051274:Glucose Transporter Type 3 / Q000187:drug effects / Q000235:genetics*; D006019:Glycolysis; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010085:Oxidative Phosphorylation; D019289:Pyruvic Acid / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D020533:Angiogenesis Inhibitors; D051274:Glucose Transporter Type 3; C495687:SLC2A3 protein, human; D000068258:Bevacizumab; D019289:Pyruvic Acid; D005947:Glucose