A significant role of lipogenic enzymes in colorectal cancer.

In this review, we summarize recent progress regarding the study of the main enzymes of lipid metabolism involved in colorectal cancer development, namely of a) farnesyltransferase (Ftase), a cytosolic enzyme that catalyzes the first step in the protein farnesylation; b) farnesyl diphosphate synthase (FPPS, which yields FPP, a substrate for Ftase; c) fatty acid synthase (FAS), an enzyme required for the conversion of acetyl-CoA and malonyl-CoA to palmitate; and d) lipoprotein lipase (LPL), the crucial enzyme for intravascular catabolism of triglyceride-rich lipoproteins. Alterations in the levels of these enzymes may contribute to a cell growth advantage acquired during the carcinogenic process and to the development of malignancy. We have demonstrated an elevated Ftase activity in human colorectal cancer (CRC), with differences in Ftase activity related to histological grading, tumor location and KRAS mutation status. Moreover, the first evidence of FPPS activity in human CRC was demonstrated by our study, where a higher FPPS activity and mRNA expression was present in cancer rather than in normal mucosa. We also detected a hyperactivation of FAS in colon cancer, related to tumor location, sex and, p53 mutation status. Our data reinforce the role of lipid metabolism in the regulation of cellular metabolic processes and in carcinogenesis. Moreover, our findings suggest that biological factors including sex, gene mutation status, as well as the stratification of patients with colorectal cancer into right- and left-sided subsets may be important in patient selection for targeted therapies. Our studies in vitro demonstrated that FAS might also be a molecular target for the antiproliferative activity of olive oil polyphenols in a metabolically defined subset of patients with colon cancer. Moreover, we detected that the serum levels of FAS in patients with colorectal cancer are associated with tumor stage. Recently, we found a significant reduction in the levels of FAS and another lipogenic enzyme, LPL, in adipose tissue adjacent to tumor lesions, compared to the levels of FAS detected in paired tissue distant from neoplasia in patients with colorectal cancer. The study of metabolic changes in lipogenic enzyme pathways, as well as the determination of the distribution of individual roles within each biochemical pathway provide a rationale for selecting a particular reaction step suitable for therapeutic intervention.