Peroxisome Proliferator-Activated Receptor ; Inhibition Prevents Adhesion to the Extracellular Matrix and Induces Anoikis in Hepatocellular Carcinoma Cells

Activation of the nuclear transcription factor peroxisome proliferator-activated receptor ; (PPAR;) inhibits growth and survival of hepatocellular carcinoma (HCC) cell lines. To further investigate the function of PPAR; in HCC, PPAR; expression patterns in primary tumors were examined, and the responses of two HCC cell lines to PPAR; activation and inhibition were compared. PPAR; expression was increased in HCC and benign-appearing peritumoral hepatocytes compared with remote benign hepatocytes. Both compound PPAR; inhibitors and PPAR; small interfering RNAs prevented HCC cell lines from adhering to the extracellular matrix. Loss of adhesion was followed by caspase-dependent apoptosis (anoikis). PPAR; inhibitors had no effect on initial B1 integrin-mediated adhesion, or on total focal adhesion kinase levels but did reduce focal adhesion kinase phosphorylation. The PPAR; inhibitor T0070907 was significantly more efficient at causing cancer cell death than the activators troglitazone and rosiglitazone. T0070907 caused cell death by reducing adhesion and inducing anoikis, whereas the activators had no direct effect on adhesion and caused cell death at much higher concentrations. In conclusion, PPAR; overexpression is present in HCC. Inhibition of PPAR; function causes HCC cell death by preventing adhesion and inducing anoikis-mediated apoptosis. PPAR; inhibitors represent a potential novel treatment approach to HCC. (Cancer Res 2005; 65(6): 2251-9)