Pancreatic cancer cell proliferation is phosphatidylinositol 3-kinase dependent

Background. Genetic mutations found in pancreatic cancer (K-ras, p16, p53) lead to inappropriate cellular proliferation. Mitogens stimulate proliferat ion via the phosphatidylinositol 3-kinase (PI3K)- and/or the p44/42-mitogen -activate protein kinase [p44/42-MAPK or extracellular signal-regulated kin ase (ERK)] signaling pathways. We examined whether inhibition of either PI3 K or ERK could limit proliferation in human pancreatic cancer. Methods. Proliferation was stimulated in quiescent human pancreatic cancer cell lines (BxPC3 and Panc-1) by 10% fetal calf serum (FCS), In certain sam ples, PD98059 (an ERK inhibitor) or LY294002 (a PI3K inhibitor) was also ad ded. AKT phosphorylation (indicating PI3K activity) and ERK phosphorylation (ERK activation) were determined by Western blot. Cell viability was deter mined by MTT assay. Cell cycle progression and apoptosis were determined by flow cytometry, A two-tailed t test was used for statistical analysis of t he data (significance P < 0.05). Results. LY294002 inhibited the PI3K pathway without affecting ERK activati on in response to serum. PD98059 inhibited the ERK pathway specifically. In both BxPC-3 and Panc-1 cell lines, LY294002 inhibited serum-induced prolif eration. This was associated with G(1) cell cycle arrest and with an increa se in the rate of apoptosis, PD98059 inhibited proliferation only in BxPC3 cells, and to a lesser degree than did LY294002, Conclusions. PI3K signaling appears to be necessary for G(1)-to-S phase pro gression and proliferation in pancreatic cancer cells. ERK plays a lesser r ole in mitogen-induced proliferation. Pharmacological inhibition of PI3K ma y decrease proliferation, increase apoptosis, and potentially confer therap eutic benefit in pancreatic cancer. (C) 2000 Academic Press.