Adenylate Cyclase/cAMP Pathway Downmodulation Counteracts Apoptosis Induced by IFN- α in Human Epidermoid Cancer Cells

We have reported previously that interferon-α (IFN-α) induces apoptosis that is counteracted by an epidermal growth factor (EGF→) Ras → extracellular signal-regulated kinase (ERK)-dependent survival response in human epidermoid cancer KB cells. We have studied the effects of the cytokine on the cAMP-dependent pathway in these cells. A decrease in the intracellular cAMP levels was recorded in KB cells treated with IFN-α, whereas forskolin induced an increase in the production of cAMP that was reduced in the presence of IFN-α, suggesting a reduction in the activity of adenylate cyclase (AC) induced by IFN-α. These effects were paralleled by significant change in the expression of some AC catalytic subunit(s) and by reduction in the activity of protein kinase A (PKA). 8-Br-cAMP completely antagonized the reduction of PKA activity induced by IFN-α, whereas PKA inhibitor KT5720 enhanced the reduction of the enzyme activity induced by IFN-α. We have found that IFN-α induced a decrease in cAMP response element binding protein (CREB) phosphorylation without changes in its total expression. The concomitant treatment with IFN-α and 8-Br-cAMP potentiated and KT5720 counteracted apoptosis induced by IFN-α alone. In conclusion, these data suggest that the decrease in AC/cAMP pathway activity is a survival response to the apoptosis induced by IFN-α. Therefore, this pathway could represent a target to enhance the antitumor activity of IFN-α.