Forskolin and phorbol ester have opposite effects on the expression of mucin-associated sialyl-Lewis(a) in pancreatic cancer cells.
The carbohydrate antigen sialyl-Lewis(a) is important to pancreatic tumour biology because the circulating antigen is used in serological tests for malignancy and because cell surface antigen is involved in tumour cell binding to the endothelial adhesion molecule, E-selectin, in extravasation. In this study, we examined the effects of the adenylyl cyclase activator, forskolin, and the diacylglycerol analogue, phorbol 12-myristate 13-acetate (PMA), on the expression and release of sialyl-Lewis(a) in human pancreatic cancer cells. Increases in the release of sialyl-Lewis(a) from SW1990 cells produced by forskolin and PMA were associated with increases in the activities of protein kinases A and C, respectively, and could be blocked by inhibitors specific for these enzymes. Immunoprecipitation experiments showed that sialyl-Lewis(a) was associated with MUC1 mucin. Forskolin also increased the cellular content of antigen and MUC1 mRNA. Actinomycin D and a protein kinase A inhibitor, H8, blocked these effects. In contrast, PMA reduced cellular antigen and MUC1 mRNA levels, although it produced a temporary increase in release of the antigen. The effects of PMA were blocked by the protein kinase C inhibitor, H7. PMA also reduced cell binding to the adhesion molecule E-selectin. In summary, PKA and PKC alter cell MUC1-associated sialyl-Lewis(a) in opposite directions. These changes may have clinical utility in the diagnosis of pancreatic cancer and the prevention of metastases.
Yamashita
Y
Y
First Department of Surgery, Osaka City University Medical School, Japan.
Ho
J J
JJ
Farrelly
E R
ER
Hirakawa
K
K
Sowa
M
M
Kim
Y S
YS
D015153:Blotting, Western; D005576:Colforsin / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D006801:Humans; D018396:Mucin-1 / Q000378:metabolism*; D009844:Oligosaccharides / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D010703:Phorbol Esters / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D000080506:Sialyl Lewis X Antigen; D014407:Tumor Cells, Cultured
D018396:Mucin-1; D009844:Oligosaccharides; D010703:Phorbol Esters; D012333:RNA, Messenger; D000080506:Sialyl Lewis X Antigen; D003609:Dactinomycin; D005576:Colforsin; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C