Loss of stearoyl‐CoA desaturase expression is a frequent event in prostate carcinoma

Abstract

Prostate carcinogenesis is influenced by genetic alterations resulting in a biochemical condition that favors cell proliferation and survival. Studies of prostate carcinoma using comparative genomic hybridization and cDNA microarray analysis indicate that numerous biochemical processes may be affected during cellular transformation and progression to an invasive phenotype. Among the consistently observed tumor-associated changes are alterations in fatty acid metabolism that influence diverse cellular activities such as signaling, energy utilization, and membrane fluidity. Increases in fatty acid synthase (FAS) levels have been shown to be one of the earliest and most frequent molecular alterations in prostate carcinogenesis. We sought to identify tumor-associated changes in the expression of genes with functional roles associated with lipid metabolism. Defined populations of normal and neoplastic prostate epithelium were acquired by laser capture microdissection and transcript levels were measured by cDNA microarray hybridization. We determined that stearoylCoA desaturase (SCD) transcripts were downregulated in cancer relative to normal epithelium. These results were confirmed by quantitative PCR. Further analysis by immunohistochemical evaluation of radical prostatectomy samples employed a quantitative scoring system with a range of 0 -300. The median SCD expression levels were 150, 45 and 10 for normal, PIN and carcinoma samples, respectively. Statistically significant differential SCD expression between normal and cancerous epithelium was determined at the p ‫؍‬ 0.001 level, and between PIN and prostate carcinoma at the p ‫؍‬ 0.03 level. Of these cases, 92% overexpressed fatty acid synthase (FAS) in cancerous cells and 84.7% exhibited the signature of FAS overexpression and SCD loss in prostate carcinoma as compared to normal prostate epithelium. These results indicate that loss of SCD expression is a frequent event in prostate adenocarcinoma, and further supports a role for altered lipid metabolism as a factor in the process of carcinogenesis.

Quantitative Proteomics Reveals That Enzymes of the Ketogenic Pathway Are Associated with Prostate Cancer Progression

“…Interestingly, the highest levels of fatty acid synthase are associated with androgen-independent bone metastatic lesions (51). Other frequently described fatty acid oxidation pathway protein alterations observed in prostate cancer include a loss of stearoyl-CoA desaturase expression and increases in D-functional protein and ␣-methylacyl-CoA racemase expression (52)(53)(54). ␣-methylacyl-CoA racemase expression in particular has been associated with increased prostate cancer risk (54,55).…”

Role of stearoyl-CoA desaturases in obesity and the metabolic syndrome

“…58 In contrast, strongly downregulated or even diminished SCD1 expression is often seen in human prostate carcinoma. 68 Interestingly, fatty acid synthase is highly upregulated in both SV40 transformed fibroblast and prostate carcinoma, as well as in many other tumor types. 22,58,69 Inhibition of fatty acid synthase is linked to induced cell death, [70][71][72] whereas overexpression predicts prostate cancer progression.…”

Inter-related in vitro effects of androgens, fatty acids and oxidative stress in prostate cancer: A mechanistic model supporting prevention strategies

“…This suggests that androgens may regulate the utilization of an alternative energy production pathway, likely via fatty acid oxidation (18). Accordingly, several well documented alterations in the expression and/or activity of enzymes involved in this pathway characterize PC: loss of stearoyl-CoA desaturase (SCD) (19), an enzyme involved in the synthesis of mono-saturated fatty acids, causes accumulation of palmitate. This is a negative regulator of ACC, which consequently reduces the level of malonyl-CoA and thereby increasing the activity of CPTI, which is the rate-limiting step in fatty acid oxidation (20).…”