Natural killer (NK) cells are lymphocytes capable of destroying
tumor cells and virally-infected cells without prior sensitization. In a previous study, we found that inhibition of
adenylyl cyclase (AC) or
cAMP-dependent protein kinase (PKA) decreased the ability of NK cells to destroy
tumor cells. We also found that the environmental contaminant
tributyltin (TBT), at concentrations of 300-500 nM, decreased
tumor-cell lysis by NK cells, as well as their intracellular levels of cAMP. This suggested that the decreases in cAMP associated with TBT (300-500 nM) may, in part, be responsible for loss of cytotoxic function. Here, we investigated the effects of inhibition of AC or PKA on
enzymes that are required in the NK tumorolytic process and compared them to those of TBT exposure. The
enzymes studied were: the
protein tyrosine kinase (PTK), syk;
phospholipase C gamma1 (PLCgamma1); and the
mitogen activated protein kinase (MAPK), p44/42. Exposure of NK cells to the AC inhibitor
2',5'-dideoxyadenosine (
DDA) significantly increased the total level of PLCgamma1 by 67% after 60 min and the level of p44/42 by about 30%. Exposure to the
PKA inhibitor H-89 significantly increased the levels of the phosphorylated (activated) p44/42 (90%) after 60 min. Exposure to TBT increased the levels of PLCgamma1 by about 50%. Previously, we found that exposure to TBT increased the phosphorylation of p44/42 within 5 min. These results indicate that AC inhibition caused alterations of the levels of key
enzymes, while decreased PKA activity caused an increase in p44/42 activation. They also suggest that the effects of decreased levels of cAMP on these key cytotoxic signaling
proteins may overlap, to a very limited extent, with those of TBT.