The phosphatidylinositol 3-kinase/AKT signal transduction pathway plays a critical role in the expression of p21(WAF1/CIP1/SDI1) induced by cisplatinand paclitaxel

The cyclin-dependent kinase inhibitor p21(WAF1/CIP1/SD11) (p21) plays a cru cial role in DNA repair, cell differentiation, and apoptosis through regula tion of the cell cycle, A2780 human ovarian carcinoma cells, which are sens itive to cisplatin and paclitaxel, express wild-type p53 and exhibit a p53- mediated increase in p21 in response to the chemotherapeutic agents. Here, we demonstrate that phosphatidylinositol 3-kinase (PI3K) and its downstream targets serine/threonine kinases AKT1 and AKT2 (AKT), are required for the full induction of p21 in A2780 cells treated with cisplatin or paclitaxel, Inactivation of the PI3K/AKT signal transduction pathway either by its spe cific inhibitor LY294002 or by expression of dominant negative AKT inhibite d p21 expression but had no inhibitory effect on the expression of the proa poptotic protein BAX by cisplatin and paclitaxel treatment. In addition, ov erexpression of wild-type or constitutively active AKT in A2780 cells susta ined the regulation of p21 induction or increased the level of p21 expressi on, respectively. Experiments with additional ovarian carcinoma cell lines revealed that PI3K is involved in the expression of p21 induced by cisplati n or paclitaxel in OVCAR-10 cells, which have wild-type p53, but not in OVC AR-5 cells, which lack functional p53, These data indicate that the PI3K/AK T signal transduction pathway mediates p21 expression and suggest that this pathway contributes to cell cycle regulation promoted by p53 in response t o drug-induced stress. However, inactivation of PI3K/AKT signaling did not result in significant alteration of the drug sensitivity of A2780 cells, su ggesting that the cell death induced by cisplatin or paclitaxel proceeds in dependently of cell protective effects of PI3K and AKT.