This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Altered fatty acid metabolism is a common feature of cancers, especially prostate cancer. In tumor cells, most fatty acids are synthesized de novo by fatty acid synthase (FASN), whereas in normal tissue, most of the fatty acids are supplied through the diet and FASN expression is almost undetectable. In prostate tumors, despite the high levels of ambient fatty acids, FASN is abundantly expressed. Our group and others showed that prostate tumors overexpressing-FASN display aggressive biological behavior. Inhibition of FASN via siRNA or chemical inhibitors, results in tumor apoptosis. The inhibitors act impairing one of the seven catalytic site of FASN, halting the production of its most abundant product, palmitate. Importantly, the cytostatic and apoptotic effects of the inhibitors are rescued when palmitate is added to the cells. Fatty acylation, i.e. protein modification by addition of fatty acids, is a common feature of eukaryotic cells. Specifically, palmitoylation is the posttranslational addition of long chain fatty acid to a cysteine residue via thioester linkage. Palmitoylation is a reversible process, and it allows for rapid regulation of protein, similar to phosphorylation. Critical signaling proteins involved in cancer are known to be palmitoylated such as Ras, Src family members (i.e. p59fyn or p56lck) and Wnt. Addition of palmitate is a signal for cellular membrane localization and is also exploited to regulate synapses, transmembrane proteins and signaling peptides. Since the effects of FASN inhibition like apoptosis or in vivo growth arrest, can be partially rescued by palmitate we proposed that cancer cells might rely on palmitate metabolism to maintain their malignant phenotype.
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