Farnesyl transferase inhibitor (R115777)-induced inhibition of STAT3(Tyr705) phosphorylation in human pancreatic cancer cell lines require extracellular signal-regulated kinases.
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.
Venkatasubbarao
Kolaparthi
K
Department of Medicine, Division of Medical Oncology, University of Texas Health Center, San Antonio, Texas 78229-3900, USA.
Choudary
Ahsan
A
Freeman
James W
JW
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors; D048708:Cell Growth Processes / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051231:Farnesyltranstransferase; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors; D015363:Quinolones / Q000494:pharmacology*; D050796:STAT3 Transcription Factor; D012694:Serine / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D000093242:Interleukin-6 Inhibitors
D019883:Alkyl and Aryl Transferases; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D051231:Farnesyltranstransferase; D015850:Interleukin-6; D016271:Proto-Oncogene Proteins c-myc; D015363:Quinolones; D050796:STAT3 Transcription Factor; D012694:Serine; D015534:Trans-Activators; D014443:Tyrosine; D000093242:Interleukin-6 Inhibitors; C493956:CDKN1A protein, human; C489427:MYC protein, human; C494086:STAT3 protein, human; C402769:tipifarnib