DOWN-REGULATION OF A HUMAN COLONIC SIALYLTRANSFERASE BY A SECONDARY BILE-ACID AND A PHORBOL ESTER

Fecal constituents such as bile acids and increased sialylation of mem brane glycoproteins by alpha-2,6-sialyltransferase (HST6N-1) may contr ibute to colorectal tumorigenesis. We hypothesized that bile acids and phorbol ester [12-O-tetradecanoylphorbol-13-acetate (TPA)] would upre gulate HST6N-1 in colonic cells. However, deoxycholate (DOG) (300 mu m ol/l), a secondary bile acid, and TPA (20 ng/ml) decreased expression of an similar to 100-kDa glycoprotein bearing alpha-2,6-linked sialic acid in a colon cancer cell line (T84) in vitro. HST6N-1 mRNA levels w ere reduced similar to 80% by treatment (less than or equal to 24 h) w ith DOC or TPA but not by cholate, a primary bile acid. Treatment (24 h) with DOC or TPA decreased activity of this enzyme to 30% and 13% of control, respectively. These effects of DOC and TPA were transcriptio nal and were mediated by Ca2+ and protein kinase C, respectively. Thus DOC and TPA both downregulated, and did not upregulate, alpha-2,6-sia lyltransferase expression in vitro, but by different transduction path ways. As colorectal tumors grow, their progressive removal from the fe cal milieu that normally downregulates this enzyme may favor invasion and metastasis.