title: Molecular mechanisms of fenofibrate-induced metabolic catastrophe and glioblastoma cell death.
abstract: Fenofibrate (FF) is a common lipid-lowering drug and a potent agonist of the peroxisome proliferator-activated receptor alpha (PPARα). FF and several other agonists of PPARα have interesting anticancer properties, and our recent studies demonstrate that FF is very effective against tumor cells of neuroectodermal origin. In spite of these promising anticancer effects, the molecular mechanism(s) of FF-induced tumor cell toxicity remains to be elucidated. Here we report a novel PPARα-independent mechanism explaining FF's cytotoxicity in vitro and in an intracranial mouse model of glioblastoma. The mechanism involves accumulation of FF in the mitochondrial fraction, followed by immediate impairment of mitochondrial respiration at the level of complex I of the electron transport chain. This mitochondrial action sensitizes tested glioblastoma cells to the PPARα-dependent metabolic switch from glycolysis to fatty acid β-oxidation. As a consequence, prolonged exposure to FF depletes intracellular ATP, activates the AMP-activated protein kinase-mammalian target of rapamycin-autophagy pathway, and results in extensive tumor cell death. Interestingly, autophagy activators attenuate and autophagy inhibitors enhance FF-induced glioblastoma cytotoxicity. Our results explain the molecular basis of FF-induced glioblastoma cytotoxicity and reveal a new supplemental therapeutic approach in which intracranial infusion of FF could selectively trigger metabolic catastrophe in glioblastoma cells.
authors.affiliation: Neurological Cancer Research, LSU Health Sciences Center, New Orleans, Louisiana, USA Stanley S. Scott Cancer Center, LSU Health Sciences Center, New Orleans, Louisiana, USA Department of Medicine, LSU Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Wilk
authors.affiliation: Neurological Cancer Research, LSU Health Sciences Center, New Orleans, Louisiana, USA Stanley S. Scott Cancer Center, LSU Health Sciences Center, New Orleans, Louisiana, USA Department of Medicine, LSU Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Dorota
authors.initials: D
authors.lastname: Wyczechowska
authors.affiliation: Neurological Cancer Research, LSU Health Sciences Center, New Orleans, Louisiana, USA Stanley S. Scott Cancer Center, LSU Health Sciences Center, New Orleans, Louisiana, USA Department of Medicine, LSU Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Adriana
authors.initials: A
authors.lastname: Zapata
authors.affiliation: Neurological Cancer Research, LSU Health Sciences Center, New Orleans, Louisiana, USA Stanley S. Scott Cancer Center, LSU Health Sciences Center, New Orleans, Louisiana, USA Department of Medicine, LSU Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Dean
authors.affiliation: Department of Pediatrics, Hematology/Oncology, University of Louisville, Louisville, Kentucky, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Mullinax
authors.affiliation: Department of Medicine, LSU Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Luis
authors.initials: L
authors.lastname: Marrero
authors.affiliation: Stanley S. Scott Cancer Center, LSU Health Sciences Center, New Orleans, Louisiana, USA Department of Medicine, LSU Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Parsons
authors.affiliation: Neurological Cancer Research, LSU Health Sciences Center, New Orleans, Louisiana, USA Stanley S. Scott Cancer Center, LSU Health Sciences Center, New Orleans, Louisiana, USA Department of Medicine, LSU Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Francesca
authors.initials: F
authors.lastname: Peruzzi
authors.affiliation: Department of Medicine, LSU Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Culicchia
authors.affiliation: Stanley S. Scott Cancer Center, LSU Health Sciences Center, New Orleans, Louisiana, USA Department of Medicine, LSU Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Augusto
authors.initials: A
authors.lastname: Ochoa
authors.affiliation: Department of Food Biotechnology, Faculty of Food Technology, Agricultural University of Krakow, Krakow, Poland.
authors.forename: Maja
authors.initials: M
authors.lastname: Grabacka
authors.affiliation: Neurological Cancer Research, LSU Health Sciences Center, New Orleans, Louisiana, USA Stanley S. Scott Cancer Center, LSU Health Sciences Center, New Orleans, Louisiana, USA Department of Medicine, LSU Health Sciences Center, New Orleans, Louisiana, USA kreiss@lsuhsc.edu.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Reiss
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001253:Astrocytes / Q000166:cytology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D016923:Cell Death; D045744:Cell Line, Tumor; D004579:Electron Transport; D005260:Female; D011345:Fenofibrate / Q000494:pharmacology*; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D006019:Glycolysis; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism; D009368:Neoplasm Transplantation; D010100:Oxygen / Q000378:metabolism; D010101:Oxygen Consumption; D047493:PPAR alpha / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D047493:PPAR alpha; D000255:Adenosine Triphosphate; D010100:Oxygen; D011345:Fenofibrate