Suppression of depleted uranium-induced neoplastic transformation of humancells 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 applicat ions. 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 uraniu m is used in military applications, it would therefore be beneficial to ide ntify and test potential antitumor-promoting agents. Chemopreventive interv entions that target deregulated signal transduction pathways may be effecti ve strategies to prevent carcinogenesis. Since the RAS protein plays a key role in signal transduction, disruption of its signaling pathway may be par ticularly effective. The phenyl fatty acid, phenyl acetate, a differentiati on inducer that affects post-translational processing of RAS, was tested fo r its ability to prevent depleted uranium-induced neoplastic transformation using HOS cells. After a 24-h exposure to insoluble depleted uranium-urani um 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 u ranium and then treated with phenyl acetate did not exhibit transformation to the tumorigenic phenotype, These data suggest that depleted uranium-indu ced neoplastic transformation in vitro can be prevented by targeting the RA S protein. (C) 2001 by Radiation Research Society.