FAS expression inversely correlates with the expression of PTEN and an Akt inhibitor synergizes with FAS siRNA to induce apoptosis in prostate cancer cells

2260 Fatty Acid Synthase (FAS), a key enzyme of the fatty acid biosynthetic pathway, has been shown to be overexpressed in various types of human cancer, and is therefore, considered to be an attractive target for anti-cancer therapy. However, relatively little is known about the regulatory mechanisms of the FAS gene in human tumor, and understanding these mechanisms is of paramount interest to design intervention of the FAS enzymatic pathway. Thus far, several factors including androgen, epidermal growth factor (EGF), PTEN and p53 have been demonstrated to modulate the expression of the FAS gene in vitro , however, none of these results have been validated in the clinical setting. In the present study, by immunohistochemical analysis of 81 prostate cancer specimens, we demonstrate that expression of the tumor suppressor gene PTEN has a significant inverse correlation with FAS expression in vivo . Furthermore, we used siRNA to inhibit the PTEN gene expression in vitro and found that knocking down the PTEN gene leads to overexpression of FAS in vitro . Together, these results suggest that the tumor suppressor gene, PTEN, negatively regulates the expression of the FAS gene. Our immunohistochemical analysis followed by Cox regression analysis also revealed that the combination of PTEN and FAS gene expression was an independent prognostic marker for prostate cancer. These data underscore the prognostic importance of combination of the FAS and PTEN genes, and also point toward the clinical relevance of the PTEN-FAS pathway in prostate tumorigenesis. As an initial trial for therapeutic targeting, we also used siRNA specific to the FAS gene in vitro . Our results indicated that the treatment of prostatic tumor cells with FAS siRNA leads to growth inhibition followed by apoptosis. Furthermore, in order to explore the possibility that the PTEN signaling pathway can be utilized to synergize the FAS siRNA mediated apoptosis, we introduced FAS siRNA and PI3K inhibitor into prostate cancer cells, and found that the PI3K inhibitor indeed synergized the effect of siRNA leading to tumor cell death. These results provide a strong rationale for exploring the therapeutic use of an inhibitor of the PTEN signaling pathway in conjunction with the FAS siRNA to inhibit prostate tumor growth.