6-ketoprostaglandin-f1-alpha and Cell-Transformation--Neoplastic

The induced synthesis of bioactive prostanoids downstream of cyclooxygenase-2 (COX-2) and prostaglandin H(2) (PGH(2)) exerts a critical event in colorectal carcinogenesis. Here we demonstrate that APC(Min/+) mice with genetic deletion of microsomal prostaglandin E synthase-1 (mPGES-1), which catalyses the terminal conversion of PGH(2) into PGE(2), surprisingly develop more and generally larger intestinal tumors than do mPGES-1 wild type littermates (mean number of tumors/intestine 80 vs. 38, p<0.0005, mean tumor diameter 1.64 vs. 1.12 mm, p<0.0005). No deviation regarding the expression of other PGE(2) related enzymes (COX-1, COX-2, mPGES-2, cPGES, and 15-PGDH) or receptors (EP1-4) was obvious among the mPGES-1 deficient mice. PGE(2) levels were suppressed in tumors of mPGES-1 deficient animals, but the concentrations of other PGH(2) derived prostanoids were generally enhanced, being most prominent for TxA(2) and PGD(2). Thus, we hypothesise that a redirected synthesis towards other lipid mediators might (over)compensate for loss of mPGES-1/PGE(2) during intestinal tumorigenesis. Nevertheless, our results question the suitability for mPGES-1 targeting therapy in the treatment or prevention of colorectal cancer.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cell Transformation, Neoplastic; Colorectal Neoplasms; Dinoprostone; Female; Gene Deletion; Intramolecular Oxidoreductases; Male; Mice; Mice, Mutant Strains; Prostaglandin-E Synthases; RNA, Messenger; Thromboxane B2

In these studies, we performed experiments designed to elucidate the role that arachidonic acid metabolism plays in oncogenic transformation in vitro. The levels of TxB2 and 6-keto-PGF1 alpha were elevated in cells treated with X-rays. A significant increase in the levels of these eicosanoids was observed following irradiation. Treatment of cells with the anticarcinogenic protease inhibitors, Bowman-Birk Inhibitor (BBI) and N-tosyl-L-phenylalanine chloromethyl ketone (TPCK), significantly reduced the levels of TxB2 and 6-keto-PGF1 alpha present. Indomethacin treatment significantly reduced the levels of TxB2 and 6-keto-PGF1 alpha to < 10% of those present in untreated or irradiated cells. We also report that addition of lipoxygenase or minoxidil [a selective inhibitor of prostacyclin (PGl2) synthetase] led to a highly significant decrease in transformation. In addition, minoxidil treatment resulted in a significant reduction in the levels of 6-keto-PGF1 alpha in irradiated cells. Our results suggest the hypothesis that the relative levels of 6-keto-PGF1 alpha are important in radiation induced transformation.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acids; Cell Line; Cell Transformation, Neoplastic; Indomethacin; Mice; Mice, Inbred C3H; Minoxidil; Models, Biological; Protease Inhibitors; Thromboxane B2; Tosylphenylalanyl Chloromethyl Ketone; Trypsin Inhibitor, Bowman-Birk Soybean; X-Rays

Plasma calcitonin and 6-oxo-Prostaglandin-F1 alpha (6-oxo-PGF1 alpha), one of the stable metabolite of prostacyclin, were determined in patients with malignant and non-malignant diseases of the lung. 11 out of 14 patients with small cell carcinoma and only 3 out of 17 patients with other histological types of lung cancer had abnormally elevated plasma calcitonin levels. 6-oxo-PGF1 alpha levels were significantly higher in patients with different types of lung cancer, compared to a control group with non-malignant lung disease. Combining the results of calcitonin and 6-oxo-PGF1 alpha measurements led to improved specificity and efficiency for the correct differentiation between small cell and non-small cell carcinoma of the lung; the predictive value for the diagnosis of small cell carcinoma approached 90%.

Topics: 6-Ketoprostaglandin F1 alpha; Calcitonin; Carcinoma, Small Cell; Cell Transformation, Neoplastic; Female; Humans; Lung Neoplasms; Male