ROS accumulation and IGF-IR inhibition contribute to fenofibrate/PPARα -mediated inhibition of Glioma cell motility in vitro

The effects of fenofibrate on Glioma cell motility, IGF-I receptor (IGF-IR) signaling, PPARα activity, reactive oxygen species (ROS) metabolism, mitochondrial potential, and ATP production were analyzed in human glioma cell lines.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 PPARα-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.Our results indicate that although fenofibrate-mediated inhibition of the IGF-IR may not be sufficient in counteracting Glioma cell dispersal, PPARα-dependent metabolic switch and the resulting ROS accumulation strongly contribute to the inhibition of these devastating brain tumor cells.Glial neoplasms account for nearly 50% of adult primary brain tumors, and Glioblastoma multiforme (GBM) is considered one of the most malignant type of CNS tumors [1,2]. GBMs originate from glial cells in the brain and/or spinal cord, and are characterized by rapid cell growth, resistance to radio- and chemo-therapies, and relentless spread of neoplastic cells within the CNS [1]. Currently, the treatments that prolong to some extent the survival of GBM patients are invasive surgery, and aggressive radiotherapy, followed by chemotherapy (temolozomid [3,4]); treatment with antibodies and inhibitors (imatinib, getifinib, avastin [5]), or anti-growth factor therapy (for instance antisense strategies against IGF-I or TGFβ [6,7]), which increase survival up to 18-24 months, instead of 8-11 months of classic survival if only surgery and radiotherapy are applied.GBMs are characterized by a wide variety of genomic abnorma