INCREASED SUSCEPTIBILITY OF RAS-TRANSFORMED CELLS TO PHENYLACETATE ISASSOCIATED WITH INHIBITION OF P21(RAS) ISOPRENYLATION AND PHENOTYPIC REVERSION

Alterations in the expression of res oncogenes are characteristic of a wide variety of human neoplasms. Accumulating evidence has linked ele vated res expression with disease progression and with failure of tumo rs to respond to conventional therapies, including radiotherapy and ce rtain chemotherapies. These observations led us to investigate the res ponse of ras-transformed cells to the differentiation-inducer phenylac etate (PA), Using gene transfer models, we show that PA caused cytosta sis in res-transformed mesenchymal cells, associated with increased ex pression of 2',5'-oligoadenylate synthetase, an enzyme implicated in n egative growth control. PA also induced phenotypic reversion character ized by loss of anchorage-independent growth, reduced invasiveness and increased expression of collagen alpha type 1, a marker of cell diffe rentiation. The anti-tumor activity of PA was observed in cases involv ing either Ha- or Ki-rat and was independent of the mode of oncogene a ctivation. Interestingly, in contrast to their relative resistance to radiation and doxorubicin, res-transformed cells were significantly mo re sensitive to PA than their parental cells. The profound changes in tumor cell and molecular biology were associated with reduced isopreny lation of the res-encoded p21. Our results indicate that PA can suppre ss the growth of res-transformed cells, resistant otherwise to free-ra dical based therapies, through interference with p21(ras) isoprenylati on, critical to signal transduction and maintenance of the malignant p henotype. (C) 1995 Wiley-Liss, Inc.