title: ROS accumulation and IGF-IR inhibition contribute to fenofibrate/PPARalpha -mediated inhibition of glioma cell motility in vitro.
abstract: BACKGROUND
  Glioblastomas are characterized by rapid cell growth, aggressive CNS infiltration, and are resistant to all known anticancer regimens. Recent studies indicate that fibrates and statins possess anticancer potential. Fenofibrate is a potent agonist of peroxisome proliferator activated receptor alpha (PPARalpha) that can switch energy metabolism from glycolysis to fatty acid beta-oxidation, and has low systemic toxicity. Fenofibrate also attenuates IGF-I-mediated cellular responses, which could be relevant in the process of glioblastoma cell dispersal.
  
  
  METHODS
  The effects of fenofibrate on Glioma cell motility, IGF-I receptor (IGF-IR) signaling, PPARalpha activity, reactive oxygen species (ROS) metabolism, mitochondrial potential, and ATP production were analyzed in human glioma cell lines.
  
  
  RESULTS
  Fenofibrate treatment attenuated IGF-I signaling responses and repressed cell motility of LN-229 and T98G Glioma cell lines. In the absence of fenofibrate, specific inhibition of the IGF-IR had only modest effects on Glioma cell motility. Further experiments revealed that PPARalpha-dependent accumulation of ROS is a strong contributing factor in Glioma cell lines responses to fenofibrate. The ROS scavenger, N-acetyl-cysteine (NAC), restored cell motility, improved mitochondrial potential, and increased ATP levels in fenofibrate treated Glioma cell lines.
  
  
  CONCLUSIONS
  Our results indicate that although fenofibrate-mediated inhibition of the IGF-IR may not be sufficient in counteracting Glioma cell dispersal, PPARalpha-dependent metabolic switch and the resulting ROS accumulation strongly contribute to the inhibition of these devastating brain tumor cells.
authors.affiliation: Neurological Cancer Research, Stanley S Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
authors.forename: Justyna
authors.initials: J
authors.lastname: Drukala
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Urbanska
authors.forename: Anna
authors.initials: A
authors.lastname: Wilk
authors.forename: Maja
authors.initials: M
authors.lastname: Grabacka
authors.forename: Ewa
authors.initials: E
authors.lastname: Wybieralska
authors.forename: Luis
authors.initials: L
authors.lastname: Del Valle
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Madeja
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Reiss
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D001483:Base Sequence; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D011345:Fenofibrate / Q000494:pharmacology*; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D047493:PPAR alpha / Q000502:physiology*; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*
chemical_list: D047493:PPAR alpha; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D017526:Receptor, IGF Type 1; D011345:Fenofibrate