4-methylene-2-octyl-5-oxofuran-3-carboxylic-acid and Adenocarcinoma

To investigate the relationship between fatty acid synthase (FASN) expression and the clinicopathological characteristics of Barrett's esophagus and its carcinogenesis.. FASN, a key enzyme of the fatty acid biosynthetic pathway, is overexpressed not only in various types of cancer, but also in premalignant conditions. Therefore, FASN overexpression is considered to be indicative of a possible premalignant stage.. Patients (N=354) with endoscopically and histologically proven Barrett's esophagus were enrolled. Mucin phenotyping of Barrett's esophagus, expression of FASN and COX-2, cellular proliferation, and apoptosis were evaluated immunohistochemically in biopsy samples, and factors influencing FASN expression were determined by multivariate logistic regression analysis. To evaluate if gastric reflux induces FASN expression, esophageal adenocarcinoma cells were treated with bile acid and low pH, and the effect of a FASN inhibitor on cell proliferation was assessed.. Expression of FASN protein was observed in 52.2% of patients with Barrett's esophagus by immunohistochemistry; this expression pattern was retained in esophageal adenocarcinoma. Intestinal mucin phenotype, COX-2, increased stromal angiogenesis, and elevated proliferating cell nuclear antigen index were confirmed to be positive independent factors for FASN expression. In the esophageal adenocarcinoma cell line SEG-1, FASN mRNA was induced by bile acid with low pH. Cell proliferation was strongly suppressed by the FASN inhibitor C75.. FASN is strongly expressed in the intestinal mucin phenotype of Barrett's esophagus, in which Barrett's glandular cells display elevated cellular proliferation, angiogenesis, and COX-2 expression. Exposure of the lower esophagus to bile acid with low pH may induce FASN in Barrett's esophagus.

Topics: 4-Butyrolactone; Adenocarcinoma; Aged; Antigens, CD34; Apoptosis; Barrett Esophagus; Bile Acids and Salts; Biopsy; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Chi-Square Distribution; Cyclooxygenase 2; Disease Progression; Enzyme Inhibitors; Esophageal Neoplasms; Esophagoscopy; Fatty Acid Synthase, Type I; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Hydrogen-Ion Concentration; Immunohistochemistry; Japan; Logistic Models; Male; Middle Aged; Odds Ratio; Precancerous Conditions; Proliferating Cell Nuclear Antigen; Risk Assessment; Risk Factors; RNA, Messenger; Time Factors

Lipid bodies (lipid droplets) are emerging as dynamic organelles involved in lipid metabolism and inflammation. Increased lipid body numbers have been described in tumor cells; however, its functional significance in cancer has never been addressed. Here, we showed increased number of lipid bodies in tumor tissues from patients with adenocarcinoma of colon submitted to surgical resection when compared with an adjacent normal tissue. Accordingly, increased numbers of lipid bodies were observed in human colon adenocarcinoma cell lines and in a H-rasV12-transformed intestinal epithelial cell line (IEC-6 H-rasV12) compared with nontransformed IEC-6 cells. The functions of lipid bodies in eicosanoid synthesis in cancer cells were investigated. CACO-2 cells have increased expression of cyclooxygenase-2 (COX-2) when compared with IEC-6 cells. We showed by immunolocalization that, in addition to perinuclear stain, COX-2 and prostaglandin E (PGE) synthase present punctate cytoplasmic localizations that were concordant with adipose differentiation-related protein-labeled lipid bodies. The colocalization of COX-2 at lipid bodies was confirmed by immunoblot of subcellular fractionated cells. Direct localization of PGE(2) at its synthesis locale showed that lipid bodies are sources of eicosanoids in the transformed colon cancer cells. Treatment with either aspirin or the fatty acid synthase inhibitor C75 significantly reduced the number of lipid bodies and PGE(2) production in CACO-2 and in IEC-6 H-rasV12 cells with effects in cell proliferation. Together, our results showed that lipid bodies in colon cancer cells are dynamic and functional active organelles centrally involved in PGE(2) synthesis and may potentially have implications in the pathogenesis of adenocarcinoma of colon.

Topics: 4-Butyrolactone; Adenocarcinoma; Aspirin; Caco-2 Cells; Cell Growth Processes; Colonic Neoplasms; Cyclooxygenase 2; Dinoprostone; HCT116 Cells; HT29 Cells; Humans; Lipid Metabolism; Organelles; Subcellular Fractions