Peroxisome proliferators are a class of nongenotoxic rodent hepatocarcinogens thought to induce
tumors by altering the balance between mitosis and apoptosis. 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-activated receptor alpha activation as well as the mitogenic activity of
peroxisome proliferators. We have investigated whether the ERK pathway plays a role in regulating the growth and survival altering properties of
peroxisome proliferators in primary mouse hepatocytes. Exposure of hepatocytes to
Wy-14,643 and trichloroacetate resulted in a dose-dependent phosphorylation and activation of ERK. Peroxisome proliferator-induced ERK phosphorylation was blocked when cells were pretreated with the
MEK (ERK
kinase) inhibitor,
PD098059, or the
phosphatidyl-inositol 3-kinase (PI3K) inhibitors,
LY294002 and
apigenin, suggesting that both
MEK and PI3K are involved in the initial response. The pathway leading to peroxisome proliferator-induced ERK activation is different than that induced by
phorbol ester or
EGF, since the PI3K inhibitors had no effect on ERK phosphorylation induced by these agents. Under defined culture conditions,
Wy-14,643 increased the level of
BrdU incorporation in primary hepatocytes and suppressed the incidence of apoptosis induced by
transforming growth factor beta 1. In contrast, concentrations of
PD098059 that block Wy-14,643-induced ERK phosphorylation also blocked the stimulation of
DNA replicative synthesis and suppression of apoptosis by
Wy-14,643. 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.