Fatty acid synthase: A metabolic oncogene in prostate cancer?

Abstract

In 1920, Warburg suggested that tumors consistently rely on anaerobic pathways to convert glucose to ATP even in the presence of abundant oxygen [Warberg, 1956] despite the fact that it is less efficient for energy supply than aerobic glycolysis. The reasons for this remain obscure to date. More often than not, the microenvironment of solid tumors contains regions of poor oxygenation and high acidity. In this context hypoxia can act in an epigenetic fashion, inducing changes in gene expression and in metabolism for survival. It is reasonable to assume that only the tumor cells capable of developing an unusual tolerance to limiting oxygen availability and to the acidosis resulting from excessive lactate production, can survive. In addition to the striking changes that occur in glucose metabolism, studies in human cancer patients suggest that there is often also an increase in free fatty acid turnover, oxidation and clearance [Legaspi et al., 1987; Hyltander et al., 1991]. For instance, a lipid mobilizing factor produced by tumor cells appears to be responsible for the increase in whole body fatty acid oxidation [Russell and Tisdale, 2002]. Fatty acids synthesis in tumor tissues also occurs at very high rates, as first demonstrated more than half a century ago [Medes et al., 1953]. Importantly, (14)C glucose studies have shown that in tumor cells almost all fatty acids derive from de novo synthesis despite adequate nutritional supply [Sabine and Abraham, 1967; Ookhtens et al., 1984; Weiss et al., 1986]. In addition, tumors overexpressing fatty acid synthase (FAS), the enzyme responsible for de novo synthesis of fatty acids, display aggressive biologic behavior compared to those tumors with normal FAS levels, suggesting that FAS overexpression confers a selective growth advantage. Here, we will review the roles that FAS plays in important cellular processes such as apoptosis and proliferation. In addition, speculations on the putative role of FAS in the altered metabolic pathways of prostate cancer cells will be explored. Because of the frequent overexpression of this enzyme prostate cancer, FAS constitutes a therapeutic target in this disease.

Expression analysis of imbalanced genes in prostate carcinoma using tissue microarrays

“…Further, FASN expression correlates with high Gleason scores in multivariate analysis, which is in accordance with previous reports (Shurbaji et al, 1996). These results demonstrate the validity of our experimental approach and further underline the role of FASN as a molecular marker and therapeutic target in prostate cancer as proposed previously (Baron et al, 2004).…”

Androgen Receptor Survival Signaling Is Blocked by Anti-β2-microglobulin Monoclonal Antibody via a MAPK/Lipogenic Pathway in Human Prostate Cancer Cells

“…SREBP-1 has been determined to regulate genes involved in fatty acid and cholesterol biosynthesis (27,29), whereas SREBP-2 is more specific in the control of cholesterol metabolism (30). Dysregulation of SREBPs and their downstream regulated genes such as fatty acid synthase (FAS), which has been proposed to be a metabolic oncogene (31,32), was shown to be involved in the development and progression of prostate cancer (33,34). The expression of SREBP-1 was observed to be highly elevated in clinical human prostate cancer specimens compared with nontumor prostate tissues, and this may be relevant to androgen-refractory progression (34).…”

Overexpression of fatty acid synthase in chemically and hormonally induced hepatocarcinogenesis of the rat

“…31 Regarding its low expression in most tissues, FAS inhibition is thus an interesting target for cancer therapy. [32][33][34] Although FAS is physiologically mainly expressed in the liver, the implication of FAS in hepatocarcinogenesis has not yet been investigated.…”