Authors: Anna Wilk, Katarzyna Urbanska, Maja Grabacka, Jennifer Mullinax, Cezary Marcinkiewicz, David Impastato, John J. Estrada and Krzysztof Reiss

Anna Wilk

Neurological Cancer Research; Louisiana State University Health Sciences Center; New Orleans, LA USA; Stanley S. Scott Cancer Center; Louisiana State University Health Sciences Center; New Orleans, LA USA

Katarzyna Urbanska

Ovarian Cancer Research Center and Department of Pathology and Laboratory Medicine; Perelman School of Medicine; University of Pennsylvania, Philadelphia, PA USA

Maja Grabacka

Department of Food Biotechnology; Faculty of Food Technology; Agricultural University of Krakow; Krakow, Poland

Jennifer Mullinax

Neurological Cancer Research; Louisiana State University Health Sciences Center; New Orleans, LA USA; Stanley S. Scott Cancer Center; Louisiana State University Health Sciences Center; New Orleans, LA USA

Cezary Marcinkiewicz

Department of Biology; College of Science and Technology; Temple University; Philadelphia, PA USA

David Impastato

Stanley S. Scott Cancer Center; Louisiana State University Health Sciences Center; New Orleans, LA USA

John J. Estrada

Stanley S. Scott Cancer Center; Louisiana State University Health Sciences Center; New Orleans, LA USA

Krzysztof Reiss

Corresponding author: kreiss@lsuhsc.edu
Neurological Cancer Research; Louisiana State University Health Sciences Center; New Orleans, LA USA; Stanley S. Scott Cancer Center; Louisiana State University Health Sciences Center; New Orleans, LA USA

Abstract:
Anti-neoplastic potential of calorie restriction or ligand-induced activation of peroxisome proliferator activated receptors (PPARs) has been demonstrated in multiple studies; however, mechanism(s) by which tumor cells respond to these stimuli remain to be elucidated. One of the potent agonists of PPARα, fenofibrate, is a commonly used lipid-lowering drug with low systemic toxicity. Fenofibrate-induced PPARα transcriptional activity is expected to shift energy metabolism from glycolysis to fatty acid β-oxidation, which in the long-term, could target weak metabolic points of glycolysis-dependent glioblastoma cells. The results of this study demonstrate that 25 μM fenofibrate can effectively repress malignant growth of primary glial tumor cells and glioblastoma cell lines. This cytostatic action involves G₁ arrest accompanied by only a marginal level of apoptotic cell death. Although the cells treated with 25 μM fenofibrate remain arrested, the cells treated with 50 μM fenofibrate undergo massive apoptosis, which starts after 72 h of the treatment. This delayed apoptotic event was preceded by FoxO3A nuclear accumulation, FoxO3A phosphorylation on serine residue 413, its elevated transcriptional activity and expression of FoxO-dependent apoptotic protein, Bim. siRNA-mediated inhibition of FoxO3A attenuated fenofibrate-induced apoptosis, indicating a direct involvement of this transcription factor in the fenofibrate action against glioblastoma. These properties of fenofibrate, coupled with its low systemic toxicity, make it a good candidate in support of conventional therapies against glial tumors.

Received: May 2, 2012; Accepted: June 5, 2012

Preview: