TRANSFORMATION OF MAMMALIAN-CELLS BY OVEREXPRESSING H2O2-GENERATING PEROXISOMAL FATTY ACYL-COA OXIDASE

Peroxisome proliferators induce qualitatively predictable pleiotropic responses, including development of hepatocellular carcinomas in rats and mice despite the inability of these compounds to interact with and damage DNA directly. In view of the nongenotoxic nature of peroxisome proliferators, it has been postulated that hepatocarcinogenesis by th is class of chemicals is due to a receptor-mediated process leading to transcriptional activation of H2O2-generating peroxisomal fatty acyl- CoA osidase (ACOX) in liver. To test this hypothesis, we overexpressed rat ACOX in African green monkey kidney cells (CV-1 cells) under cont rol of the cytomegalovirus promoter. A stably transfected CV-1 cell li ne overexpressing rat ACOX, designated CV-ACOX4, when exposed to a fat ty acid substrate (150 mu M linoleic acid) for 2-6 weeks, formed trans formed foci, grew efficiently in soft agar, and developed adenocarcino mas when transplanted into nude mice. These findings indicate that sus tained overexpression of H2O2-generating ACOX causes cell transformati on and provide further support for the role of peroxisome proliferatio n in hepatocarcinogenesis induced by peroxisome proliferators.