8-11-14-eicosatrienoic-acid and Carcinoma--Squamous-Cell

Cytochrome P450 epoxygenases (CYP450) have been recently shown to promote malignant progression. Here we investigated the mRNA and protein expression and potential clinical relevance of CYP2C9 in esophageal cancer. Highest expression was detected in esophageal adenocarcinoma (EAC; n=78) and adjacent esophageal mucosa (NEM; n=79). Levels of CYP2C9 in EAC and NEM were significantly higher compared to esophageal squamous cell carcinoma (ESCC; n=105). Early tumor stages and well-differentiated tumors showed a significantly higher CYP2C9 expression compared to progressed tumors. Moreover, CYP2C9 expression was correlated to high Ki-67 labeling indices in EAC and Ki-67 positive tumor cells in EAC and ESCC. Selective inhibition of CYP2C9 decreased tumor cell proliferation (KYSE30, PT1590 and OE19) in vitro, which was abolished by 11,12-epoxyeicosatrienoic acid (11,12-EET). Cell-cycle analysis using FACS revealed that inhibition of CYP2C9 leads to a G0/G1 phase cell-cycle arrest. CYP2C9 seems to be relevant for early esophageal cancer development by promoting tumor cell proliferation. Pharmacological inhibition of CYP2C9 might contribute to a more efficient therapy in CYP2C9 highly expressing esophageal cancers.

Topics: 8,11,14-Eicosatrienoic Acid; Aryl Hydrocarbon Hydroxylases; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Cytochrome P-450 CYP2C9; Disease Progression; Esophageal Neoplasms; G1 Phase; Humans; Immunohistochemistry; Resting Phase, Cell Cycle

Eicosatrienoic acid (ETA 5,8,11, n-9) is abnormally increased by essential fatty acid deficiency (EFAD), a condition associated with alterations of cell proliferation and differentiation. In comparison to certain EFAs, addition of ETA at a low concentration resulted in a reduction in the expression of the cell-cell adhesion molecule, E-cadherin, and to a lesser degree, of desmoglein, along with increased invasion of Matrigel by human squamous cell carcinoma (SCC) cells in vitro. At higher concentrations, ETA stimulated the growth of SCC cells. As previously shown, n-6 EFAs (mainly 18:3 n-6, GLA), up-regulated the expression of E-cadherin and desmoglein. This is the first report showing that the abnormal 20:3 n-9 (Mead's acid) is a down regulator of antimetastatic E-cadherin and desmoglein expression.

Topics: 8,11,14-Eicosatrienoic Acid; Bisbenzimidazole; Blotting, Western; Cadherins; Carcinoma, Squamous Cell; Cell Adhesion Molecules; Cell Division; Cytoskeletal Proteins; Desmogleins; Desmoplakins; Dose-Response Relationship, Drug; gamma-Linolenic Acid; Humans; Immunohistochemistry; Tumor Cells, Cultured