PEROXISOME PROLIFERATORS INDUCE APOPTOSIS IN HEPATOMA-CELLS

In the AH-130 hepatoma, a poorly differentiated tumor, maintained by w eekly transplantations in rats, a low percentage of cells spontaneousl y underwent apoptosis, mainly during the transition from logarithmic-t o stationary-growth phase. It was possible to induce massive apoptosis of cells by treating them with clofibrate, a peroxisome proliferator and hypolipidemic drug. Similar results were obtained with HepG2 cells . With 1 mM clofibrate, apoptosis began to manifest itself after 1 h o f treatment in vitro, and was assessed by morphological analysis, by D NA fragmentation carried out with agarose gel electrophoresis, and wit h flow cytometric determination of terminal deoxynucleotidyl transfera se-mediated dUTP-biotin nick end-labeling. The mechanisms whereby clof ibrate induces apoptosis are still unclear. Since the peroxisome proli ferator-activated receptor was expressed at a very low level and was n ot stimulated by clofibrate in the AH-130 hepatoma cells, its involvem ent seems unlikely. Moreover, lipid peroxidation was not increased aft er clofibrate treatment. Phospholipids and cholesterol were significan tly decreased. The decreased cholesterol content might suggest an inhi bition of the mevalonate pathway and, therefore, of isoprenylation of proteins involved in cell proliferation.