The extracellular signal-regulated kinase pathway contributes to mitogenicand antiapoptotic effects of peroxisome proliferators in vitro

Peroxisome proliferators are a class of nongenotoxic rodent hepatocarcinoge ns thought to induce tumors by altering the balance between mitosis and apo ptosis. Previous studies suggest mitogenic growth factors that act through the extracellular signal-regulated kinase (ERK) pathway, including insulin and epidermal growth factor (EGF), modulate peroxisome proliferator-activat ed receptor alpha activation as well as the mitogenic activity of peroxisom e proliferators. We have investigated whether the ERK pathway prays a role in regulating the growth and survival altering properties of peroxisome pro liferators in primary mouse hepatocytes. Exposure of hepatocytes to Wy-14,6 43 and trichloroacetate resulted in a dose-dependent phosphorylation and ac tivation of ERK, Peroxisome proliferator-induced ERK phosphorylation was bl ocked when cells were pretreated with the MEK (ERK kinase) inhibitor, PD098 059, or the phosphatidylinositol 3-kinase (PI3K) inhibitors, LY294002 and a pigenin, suggesting that both MEK and PI3K are involved in the initial resp onse. The pathway leading to peroxisome proliferator-induced ERK activation is different than that induced by phorbol ester or EGF, since the PI3K inh ibitors had no effect on ERK phosphorylation induced by these agents. Under defined culture conditions, Wy-14,643 increased the level of BrdU incorpor ation in primary hepatocytes and suppressed the incidence of apoptosis indu ced by transforming growth factor beta 1. In contrast, concentrations of PD 098059 that block Wy-14,643-induced ERK phosphorylation also blocked the st imulation of DNA replicative synthesis and suppression of apoptosis by Wy-1 4,643, These studies indicate that activation of the ERK pathway through a PI3K-dependent mechanism may play a significant role in the tumor-promoting properties of peroxisome proliferators, (C) 1999 Academic Press.