IFN-GAMMA INDUCTION OF P21(WAF1) IN PROSTATE-CANCER CELLS - ROLE IN CELL-CYCLE, ALTERATION OF PHENOTYPE AND INVASIVE POTENTIAL

Type I and type II interferons (IFNs) are known to exert antitumor eff ects on a variety of tissues and cell types. We have previously shown that the type I IFN IFN alpha: induces the expression of the cyclin-de pendent kinase inhibitor p21(WAFI) and inhibits the cell cycle of the human prostate adenocarcinoma cell line, DUI45, that carries mutations in the tumor suppressor gene products p53 and pRB. We now show that t he type II IFN IFN gamma similarly induces the expression of p21(WAFI) and inhibits the cell cycle of DU145 cells. In addition, we show that while both IFNs exert antiproliferative activity, only IFN gamma indu ced phenotypic changes in these cells that accompanied the antiprolife rative effect, For example, IFN gamma, but not IFN alpha, caused a sig nificant reduction in epidermal growth factor receptor expression as w ell as an increase in the adhesion molecules intercellular adhesion mo lecule-I and integrin alpha 3. These phenotypic changes in DU145 cells are suggestive of the acquisition of a non-tumorigenic se-ate. Consis tent with these findings, IFN gamma showed a significantly lower invas ive ability in in vitro assays using invasion chambers. Thus, IFN gamm a inhibits both the cell cycle and the metastatic potential of DU145 c ells independent of the p53 and RB status, and our data describe a mec hanism for mediating the antitumor capabilities of IFN gamma that bypa sses tumor suppressor genes like p53. (C) 1998 Wiley-Liss, Inc.