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.