Peroxisome proliferator activated receptor alpha inhibits hepatocarcinogenesis through mediating NF-κB signaling Pathway

Peroxisome proliferator-activated receptor alpha (PPAR alpha) ligands have been reported to suppress cancer growth. However, the role of PPAR alpha in hepatocarcinogenesis remains unclear. We investigated the functional significance of PPAR alpha in hepatocellular carcinoma (HCC). PPAR alpha-knockout (PPAR alpha(-/-)) mice were more susceptible to diethylnitrosamine (DEN)-induced HCC at 6 months compared with wild-type (WT) littermates (80% versus 43%, P < 0.05). In resected HCCs, TUNEL-positive apoptotic cells were significantly less in PPAR alpha(-/-) mice than in WT mice (P < 0.01), commensurate with a reduction in cleaved caspase-3 and caspase-7 protein expression. Ki-67 staining showed increased cell proliferation in PPAR alpha(-/-) mice (P < 0.01), with concomitant up-regulation of cyclin-D1 and down-regulation of p15. Moreover, ectopic expression of PPAR alpha in HCC cells significantly suppressed cell proliferation and induced apoptosis. The anti-tumorigenic function of PPAR alpha was mediated via NF-kappa B as evidenced by inhibition of NF-kappa B promoter activity, diminution of phosphor-p65, phosphor-p50 and BCL2 levels, and enhancing IkB alpha protein. Chromatin immunoprecipitation analysis confirmed PPAR alpha directly binds to the IkB alpha promoter. In conclusion, PPAR alpha deficiency enhances susceptibility to DEN-initiated HCC. PPAR alpha suppresses tumor cell growth by inhibiting cell proliferation and inducing cell apoptosis via direct targeting I kappa B alpha and NF-kappa B signaling pathway.