Activation of PPAR alpha inhibits IGF-I-mediated growth and survival responses in medulloblastoma cell lines

Recent studies suggest a potential role of lipid lowering drugs, fibrates and statins, in anticancer treatment. One candidate for tumor chemoprevention is fenofibrate, which is a potent agonist of peroxisome proliferator activated receptor alpha (PPAR alpha). Our results demonstrate elevated expression of PPAR alpha in the nuclei of neoplatic cells in 12 out of 13 cases of medulloblastoma, and of PPAR gamma in six out of 13 cases. Further analysis demonstrated that aggressive mouse medulloblastoma cells, BsB8, express PPAR alpha in the absence PPAR gamma, and human medulloblastoma cells, D384 and Daoy, express both PPAR alpha and PPAR gamma. Mouse and human cells responded to fenofibrate by a significant increase of PPAR-mediated transcriptional activity, and by a gradual accumulation of cells in G1 and G2/M phase of the cell cycle, leading to the inhibition of cell proliferation and elevated apoptosis. Preincubation of BsB8 cells with fenofibrate attenuated IGF-I-induced IRS-1, Akt, ERKs and GSK3 beta phosphorylation, and inhibited clonogenic growth. In Daoy and D384 cells, fenofibrate also inhibited IGF-I-mediated growth responses, and simultaneous delivery of fenofibrate with low dose of the IGF-IR inhibitor, NVP-AEW541, completely abolished their clonogenic growth and survival. These results indicate a strong supportive role of fenotibrate in chemoprevention against IGF-I-induced growth responses in medulloblastoma. (C) 2008 Wiley-Liss, Inc.