Differential response of Akt to cyclic AMP modulates drug sensitivity

Although Akt is known to be associated with drug resistance, its role in cyclic AMP (cAMP)-related inhibition of cell proliferation is not clear. Here, we report that Akt modulates the sensitivity of hepatocellular carcinoma cells to cAMP. Treatment of hepatocellular carcinoma cell lines (HepG(2) and Bel-7402) with cAMP inhibited proliferation, with HepG(2) cells showing lower sensitivity to cAMP. Biochemical studies showed that cAMP increased FBS-stimulated Akt phosphorylation in HepG(2) cells, but completely inhibited FBS-stimulated Akt phosphorylation in Bel-7402 cells, suggesting that the differential response of Akt to cAMP in these two cell lines might contribute to their differential sensitivity. LY294002, a phosphatidylinositol 3-kinase inhibitor that inhibits FBS-stimulated Akt phosphorylation, restored the sensitivity of HepG(2) cells to cAMP and API-2 (Akt/protein kinase B signaling inhibitor-2) also showed similar effect. These results collectively indicate that the response level of Akt to cAMP may play a critical role in determining drug sensitivity.