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

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 < 0.001) of pancreatic cancer cells. Inactivation of Stat3 by dominant-negative Stat3 adenovirus partly suppressed the growth of pancreatic cancer cells on day 4 post-inoculation (P < 0.05) but not the expression of these mRNAs. These results indicate that activation of the JAK/Stat3 signaling pathway plays an important role in the progression of pancreatic cancer and that blockade of JAK/Stat3 signals may provide a novel therapeutic strategy for pancreatic cancer. (C) 2003 Elsevier Ireland Ltd. All rights reserved.