Silencing of the fatty acid synthase gene by RNA interference inhibits growth and induces apoptosis of LNCaP prostate cancer cells

A screening for androgen-regulated genes in prostate cancer (PCA) cells revealed that androgenes, apart from their well known effects on cell survival, proliferation, and differentiation, stimulate the expression of several lipogenic genes, including the gene encoding fatty acid synthase (FAS). FAS, a key enzyme in the biosynthesis of fatty acids, is markedly overexpressed in many epithelial cancers including cancer of the prostate, breast, ovary and endometrium. To gain more insight into the role of FAS in cancer cells and to explore its potential as a novel target for antineoplastic therapy, we have used the potent and highly sequence-specific technique of RNA interference (RNAi) to silence FAS in LNCaP prostate cancer cells. RNAi-mediated down-regulation of FAS expression resulted in a major decrease in the synthesis of triglycerides and of phospholipids partitioning into detergent-resistant membrane microdomains. These effects were accompanied by marked morphological changes, including a reduction in cell volume, a loss of cell-cell contacts, and the formation of spider-Re extrusions. Furthermore, silencing of the FAS gene by RNAi significantly inhibited LNCaP cell growth and ultimately resulted in induction of apoptosis. In striking contrast with LNCaP cells, RNAi-mediated inhibition of FAS did not influence viability of nonmalignant fibroblasts. The data presented herein suggest that overexpression of FAS induced by hormones, growth factors, or other mechanisms may play an important role in cancer cell biology, and that RNA interference, particularly targeting lipogenic genes, constitutes a promising tool for the development of new cancer treatments.