SELECTED EICOSANOIDS INCREASE THE PROLIFERATION RATE OF HUMAN COLON-CARCINOMA CELL-LINES AND MOUSE COLONOCYTES IN-VIVO

Eicosanoids have been implicated in colon carcinogenesis, but their role remains unclear. The levels of PGE(2) are elevated in colon cancer tissues and in blood draining colon tumors. The effect of eicosanoids on the proliferation of colonic cells is unknown. We studied the effect of several prostaglandins (PGs) and leukotriene (LT)B-4 on the proliferation rate of the human colon adenocarcinoma cell lines SW1116 and HT-29 and of 16,16-dimethyl PGE(2) (dmPGE(2)) on the colon of BALB/c mice. PGs E(2), F-2 alpha, I-2, the methyl ester of PGE(2), dmPGE(2), and LTB(4) (10(-10), 10(-8), 10(-6) M), administered for up to 72 h, stimulated cell proliferation in SW1116 cells and all but PGF(2 alpha) and PGI(2) stimulated proliferation in HT-29 cells. The proliferative effect was time- and concentration-dependent. However, in SW1116 cells the response to PGs was 'bell-shaped', being maximal at 10(-8) M, with the 10(-10) and 10(-6) M concentrations being less effective. In HT-29 cells, the addition of methyl groups to the PGE(2) molecule increased the proliferative effect. None of these eicosanoids affected the distribution of these cells in the cell cycle or their rate of programmed cell death (apoptosis). dmPGE(2) stimulated 3.6-fold the proliferation of colonocytes in normal BALB/c mice. This was determined by bivariate flow cytometric analysis of the expression of proliferating cell nuclear antigen (PCNA) in virtually pure populations of mouse colonocytes. dmPGE(2) did not alter the cell cycle distribution of these cells. We conclude that several PGs as well as LTB(4) stimulate the proliferation of human colon carcinoma cells in vitro, while dmPGE(2) has a similar effect on mouse colonocytes in vivo. These findings raise the possibility that eicosanoids may contribute to colonic carcinogenesis by stimulating the proliferation rate of tumor cells in the colon.