In this study, we report that
R115777, a nonpeptidomimetic farnesyl
transferase inhibitor, suppresses the growth of human pancreatic
adenocarcinoma cell lines and that this growth inhibition is associated with modulation in the phosphorylation levels of signal transducers and activators of transcription 3 (STAT3) and
extracellular signal-regulated kinases (ERK). Treatment of cells with
R115777 inhibited the
tyrosine phosphorylation of STAT3((Tyr705)), while increasing the
serine phosphorylation of STAT3((Ser727)). We found the differential phosphorylation of STAT3 was due to an increased and prolonged activation of ERKs. The
biological significance of ERK-mediated inhibition of STAT3((Tyr705)) phosphorylation was further assessed by treating the cells with an inhibitor (
PD98059) of
mitogen-activated protein kinase kinase (
MEK) or by transfecting the cells with a vector that expresses constitutively active MEK-1. Expression of constitutively active MEK-1 caused an increase of ERK activity and inhibited STAT3((Tyr705)) phosphorylation. Conversely, inhibition of ERK activity by
PD98059 reversed the R115777-induced inhibition of STAT3((Tyr705)) phosphorylation.
R115777 also caused the inhibition of the binding of STAT3 to its consensus binding
element. An increase in the activation of ERKs either by overexpressing MEK-1 or treatment of cells with
R115777 caused an up-regulation in the levels of a
cyclin-dependent kinase (cdk) inhibitor, p21(cip1/waf1). These observations suggest that R115777-induced growth inhibition is partly due to the prolonged activation of ERKs that mediates an inhibition of STAT3((Tyr705)) phosphorylation and an increase in the levels of p21(cip1/waf1) in human pancreatic
adenocarcinoma cell lines.