Downregulation of a human colonic sialyltransferase by a secondary bile acid and a phorbol ester.
Fecal constituents such as bile acids and increased sialylation of membrane glycoproteins by alpha-2,6-sialyltransferase (HST6N-1) may contribute to colorectal tumorigenesis. We hypothesized that bile acids and phorbol ester [12-O-tetradecanoylphorbol-13-acetate (TPA)] would upregulate HST6N-1 in colonic cells. However, deoxycholate (DOC) (300 mumol/l), a secondary bile acid, and TPA (20 ng/ml) decreased expression of an approximately 100-kDa glycoprotein bearing alpha-2,6-linked sialic acid in a colon cancer cell line (T84) in vitro. HST6N-1 mRNA levels were reduced approximately 80% by treatment (< or = 24 h) with 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 transcriptional and were mediated by Ca2+ and protein kinase C, respectively. Thus DOC and TPA both downregulated, and did not upregulate, alpha-2,6-sialyltransferase expression in vitro, but by different transduction pathways. As colorectal tumors grow, their progressive removal from the fecal milieu that normally downregulates this enzyme may favor invasion and metastasis.
Li
M
M
Department of Medicine, Buffalo Veterans Affairs Medical Center, New York, USA.
Vemulapalli
R
R
Ullah
A
A
Izu
L
L
Duffey
M E
ME
Lance
P
P
D002118:Calcium / Q000378:metabolism; D002273:Carcinogens / Q000494:pharmacology*; D002478:Cells, Cultured; D003106:Colon / Q000187:drug effects / Q000201:enzymology*; D003840:Deoxycholic Acid / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D011493:Protein Kinase C / Q000378:metabolism; D012799:Sialyltransferases / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase
D002273:Carcinogens; D003840:Deoxycholic Acid; D012799:Sialyltransferases; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase