Suppression of depleted uranium-induced neoplastic transformation of human cells by the phenyl fatty acid, phenyl acetate: chemoprevention by targeting the p21RAS protein pathway.
Depleted uranium is a dense heavy metal used primarily in military applications. Published data from our laboratory have demonstrated that exposure to depleted uranium in vitro can transform immortalized human osteoblast (HOS) cells to the tumorigenic phenotype (associated with aberrant RAS oncogene expression and tumor suppressor protein production). Since depleted uranium is used in military applications, it would therefore be beneficial to identify and test potential antitumor-promoting agents. Chemopreventive interventions that target deregulated signal transduction pathways may be effective strategies to prevent carcinogenesis. Since the RAS protein plays a key role in signal transduction, disruption of its signaling pathway may be particularly effective. The phenyl fatty acid, phenyl acetate, a differentiation inducer that affects post-translational processing of RAS, was tested for its ability to prevent depleted uranium-induced neoplastic transformation using HOS cells. After a 24-h exposure to insoluble depleted uranium-uranium dioxide (1 mg/ml), cells were incubated for 1 day to 6 weeks with 2.5 mM phenyl acetate. Treatment with depleted uranium resulted in transformation to the tumorigenic phenotype. In contrast, HOS cells exposed to depleted uranium and then treated with phenyl acetate did not exhibit transformation to the tumorigenic phenotype. These data suggest that depleted uranium-induced neoplastic transformation in vitro can be prevented by targeting the RAS protein.