TY - JOUR
T1 - Blockade of constitutively activated Janus kinase/signal transducer and activator of transcription-3 pathway inhibits growth of human pancreatic cancer
AU - Toyonaga, Takayuki
AU - Nakano, Kenji
AU - Nagano, Masahiro
AU - Zhao, Gang
AU - Yamaguchi, Koji
AU - Kuroki, Syoji
AU - Eguchi, Takashi
AU - Chijiiwa, Kazuo
AU - Tsuneyoshi, Masazumi
AU - Tanaka, Masao
N1 - Funding Information:
We greatly thank Yoko Matsuzuru for technical assistance and Dr Akihiko Yoshimura (Kyushu University) for critical discussion. This work was partly supported by Grant-in-Aids for Scientific Research (#13671310 for KN; #14571208 for SK) from Japanese Ministry of Science, Culture and Technology.
PY - 2003/11/10
Y1 - 2003/11/10
N2 - 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.
AB - 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.
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U2 - 10.1016/S0304-3835(03)00482-8
DO - 10.1016/S0304-3835(03)00482-8
M3 - Article
C2 - 14580692
AN - SCOPUS:0142122338
VL - 201
SP - 107
EP - 116
JO - Cancer Letters
JF - Cancer Letters
SN - 0304-3835
IS - 1
ER -