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 (PPARa). Our results demonstrate elevated expression of PPARa in the nuclei of neoplatic cells in 12 out of 13 cases of medulloblastoma, and of PPARc in six out of 13 cases. Further analysis demonstrated that aggressive mouse medulloblastoma cells, BsB8, express PPARa in the absence PPARc, and human medulloblastoma cells, D384 and Daoy, express both PPARa and PPARc. 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 GSK3b 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 fenofibrate in chemoprevention against IGF-Iinduced growth responses in medulloblastoma. ' 2008 Wiley-Liss, Inc.Key words: PPARa; fenofibrate; IGF-I; medulloblastoma Medulloblastomas are highly malignant cerebellar tumors of the childhood, which originate from the external granule layer of the cerebellum and have an inherent tendency to spread in the CNS via cerebrospinal fluid. Medulloblastomas are characterized by a large number of genetic and epigenetic aberrations. 1 Among them, overexpression of insulin-like growth factor receptor (IGF-IR), and insulin receptor substrate 1 (IRS-1) are frequently seen in these tumors. [1][2][3][4][5] The IGF-IR is a membrane-associated tyrosine kinase capable of mediating a variety of biological responses including cell survival and cell proliferation. 6,7 In the cerebellum, the IGF-IR has been shown in the granule cell layer and in Purkinje cells, and IGF-I protected cultures of cerebellar neurons from low potassium induced apoptosis. 8,9 In medulloblastoma, the IGF-IR signaling system has been investigated quite intensively. 4,10 Resent results from our laboratory demonstrate that medulloblastoma cell lines and medulloblastoma biopsies are characterized by an abundant presence of the IGF-IR, and its major signaling molecule, IRS-1. 2,3 Importantly, we have detected the phosphorylated form of the IGF-IR (active) in the majority of medulloblastoma clinical samples examined. 2 In addition, growth and survival of medulloblastoma cell lines cultured in suspension was strongly dependent on the presence of exogenous IGF-I. 2,3 The low-molecular-weight inhibitor of the IGF-IR, NVP-AEW541, is one of the most effective inhibitors of the growth of medulloblastoma cells and induces massive apop...