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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 (PPAR?). FF and several other agonists of PPAR? 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 PPAR?-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 PPAR?-dependent metabolic switch from glycolysis to fatty acid ?-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.

SUBMITTER: Wilk A 

PROVIDER: S-EPMC4295376 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Molecular mechanisms of fenofibrate-induced metabolic catastrophe and glioblastoma cell death.

Wilk Anna A   Wyczechowska Dorota D   Zapata Adriana A   Dean Matthew M   Mullinax Jennifer J   Marrero Luis L   Parsons Christopher C   Peruzzi Francesca F   Culicchia Frank F   Ochoa Augusto A   Grabacka Maja M   Reiss Krzysztof K  

Molecular and cellular biology 20141020 1


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 me  ...[more]

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