Adenylate cyclase/cAMP pathway downmodulation counteracts apoptosis induced by IFN-alpha in human epidermoid cancer cells.

We have reported previously that interferon-alpha (IFN-a) 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-a, whereas forskolin induced an increase in the production of cAMP that was reduced in the presence of IFN-a, suggesting a reduction in the activity of adenylate cyclase (AC) induced by IFN-a. 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-a, whereas PKA inhibitor KT5720 enhanced the reduction of the enzyme activity induced by IFN-a. We have found that IFN-a induced a decrease in cAMP response element binding protein (CREB) phosphorylation without changes in its total expression. The concomitant treatment with IFN-a and 8-Br-cAMP potentiated and KT5720 counteracted apoptosis induced by IFN-a alone. In conclusion, these data suggest that the decrease in AC/cAMP pathway activity is a survival response to the apoptosis induced by IFN-a. Therefore, this pathway could represent a target to enhance the antitumor activity of IFN-a.