Adenylate cyclase/cAMP pathway downmodulation counteracts apoptosis induced by IFN-alpha in human epidermoid cancer cells.
We have reported previously that interferon-alpha (IFN-alpha) 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-alpha, whereas forskolin induced an increase in the production of cAMP that was reduced in the presence of IFN-alpha, suggesting a reduction in the activity of adenylate cyclase (AC) induced by IFN-alpha. 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-alpha, whereas PKA inhibitor KT5720 enhanced the reduction of the enzyme activity induced by IFN-alpha. We have found that IFN-alpha induced a decrease in cAMP response element binding protein (CREB) phosphorylation without changes in its total expression. The concomitant treatment with IFN-alpha and 8-Br-cAMP potentiated and KT5720 counteracted apoptosis induced by IFN-alpha alone. In conclusion, these data suggest that the decrease in AC/cAMP pathway activity is a survival response to the apoptosis induced by IFN-alpha. Therefore, this pathway could represent a target to enhance the antitumor activity of IFN-alpha.
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Department of Biochemistry and Biophysics, II University of Naples, 80138 Naples, Italy.
Spina
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Marra
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Sorrentino
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Chiosi
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Romano
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Improta
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Budillon
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Illiano
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G
Abbruzzese
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Caraglia
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D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects*; D002227:Carbazoles / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000201:enzymology*; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D016898:Interferon-alpha / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*
D002227:Carbazoles; D004791:Enzyme Inhibitors; D007155:Immunologic Factors; D007211:Indoles; D016898:Interferon-alpha; D011758:Pyrroles; D015124:8-Bromo Cyclic Adenosine Monophosphate; C057416:KT 5720; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases