Blockade of constitutively activated Janus kinase/signal transducer and activator of transcription-3 pathway inhibits growth of human pancreatic cancer

Abstract Constitutive activation of signal transducer and activator of transcription (Stat) proteins has been demonstrated in a wide variety of malignancies. In this study, we elucidated the significance of Janus kinase (JAK) and the downstream transcription factor Stat3 signals on malignant potentials of pancreatic cancer. Electrophoretic mobility shift assay and immunohistochemical analysis revealed that Stat3 was constitutively activated in subsets of human pancreatic cancer tissues and cell lines (Panc1, Kp4, AsPC-1, BxPC-3). A JAK-specific inhibitor, tyrphostin AG490, markedly inhibited Stat3 activation and expression of cyclin D1, bcl-xL and vascular endothelial growth factor mRNAs estimated by RT-PCR, as followed by growth arrest (6.3–21.3% vs controls; P P