cAMP protection of pancreatic cancer cells against apoptosis induced by ERK inhibition

Large increases in cAMP concentration inside the cell are generally growth inhibitory for most cell lines of mesenchymal and epithelial origin. Moreov er, recent data suggest a role of cAMP in survival of differ ent cell types , Herein, the ability of forskolin tan adenylyl cyclase activator) and IBMX (3-isobutyl-1-methylxanthine) (a phosphodiesterase inhibitor) to modulate cell cycle progression and survival of human pancreatic cancer cells was ev aluated. We showed that forskolin + IBMX inhibited serum-induced ERK activi ties, Rb hyperphosphorylation, Cdk2 activity, and p27(Kip1) downregulation and caused G1 arrest in MIA PaCa-2 cells. Furthermore, forskolin + IBMX pro tected pancreatic cells against apoptosis induced by prolonged inhibition o f ERK activities by preventing Bcl-X-L downregulation, activation of caspas es 3, 6, 8, and 9, and PARP cleavage and by inducing Bad phosphorylation (s er112), Taken together, our data demonstrate for the first time that cAMP i s an inhibitor of cell cycle progression and apoptosis in human pancreatic cancer cells. (C) 2001 Academic Press.