The effect of leukotrienes B and selected HETEs on the proliferation of colon cancer cells

Abstract Eicosanoids have been implicated in colon carcinogenesis, but very little is known on the potential role of leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs) in this process; such compounds are produced by colonocytes and tumor infiltrating leukocytes. We studied the effect of LTB 4 , LTB 4 methyl ester, LTB 5 , 12( R )-HETE, 12( S )-HETE and 15( S )-HETE (10 −10 , 10 −8 , 10 −6 M) on the proliferation rate, the cell cycle distribution, and the rate of apoptosis in HT-29 and HCT-15 human colon carcinoma cells. Our data show that LTB 4 , a lipoxygenase product, increased the proliferation rate of both cell lines in a time- and concentration-dependent manner. In HT-29 cells the concentration-response curve was bell-shaped (maximal effect at 10 −8 M). The proliferative effects of LTB 4 in HT-29 cells were inhibited by SC-41930, a competitive antagonist of LTB 4 , suggesting the existence of an LTB 4 receptor in epithelial cells. The methyl ester of LTB 4 stimulated the proliferation of these cells, but LTB 5 , an isomer of LTB 4 derived from eicosapentaenoic acid, did not. Of the HETEs, only 12( R )-HETE, a P -450 product, stimulated the proliferation of both cell lines; the other HETEs, all lipoxygenase products, failed to affect the proliferation of these cells. None of these eicosanoids had any effect on cell cycle distribution or apoptosis in either cell line. Taken together with our previous data showing that PGs stimulate colon cancer cell proliferation (Qiao et al. (1995) Biochim. Biophys. Acta 1258, 215–223), these findings indicate that arachidonic acid products synthesized via at least three different pathways (cyclooxygenase, lipoxygenase, P -450) may be able to modulate the growth of colon cancer, and suggest a potential role in human colon carcinogenesis for LTB 4 and 12( R )-HETE.