Jak inhibitor induces S phase cell-cycle arrest and augments TRAIL-induced apoptosis in human hepatocellular carcinoma cells.
Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in various cancers and plays a crucial role in oncogensis, including the activation of genes encoding apoptosis inhibitors and cell-cycle regulators. We investigated the biological significance of the Janus kinase (Jak)-STAT pathway in human hepatocellular carcinoma (HCC). Constitutive activation of STAT3 was seen in 49.4% of human HCC specimens and in HCC cell lines. Jak inhibitor AG490 inhibited activation of STAT3 and markedly reduced cell viability without significant apoptosis. AG490 also induced S phase cell-cycle arrest with down-regulation of cyclin D1, A, E and up-regulation of p21, p27, phospho-Chk2. AG490 also inhibited caspase inhibitory proteins, such as XIAP and survivin, and augmented TRAIL-induced apoptosis. Our study suggests that the Jak-STAT pathway plays an important role in cell-cycle progression and resistance to apoptosis. Inhibition of the Jak-STAT pathway may thus be a therapeutic target for HCC.
Fuke
Hiroyuki
H
Department of Gastroenterology, Mie University School of Medicine, 2-174, Edobashi, Tsu, Mie 514-8507, Japan.
Shiraki
Katsuya
K
Sugimoto
Kazushi
K
Tanaka
Junichiro
J
Beppu
Tetsuya
T
Yoneda
Kentaro
K
Yamamoto
Norihiko
N
Ito
Keiichi
K
Masuya
Masahiro
M
Takei
Yoshiyuki
Y
D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D053612:Janus Kinases / Q000037:antagonists & inhibitors*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D010766:Phosphorylation / Q000187:drug effects; D016196:S Phase / Q000187:drug effects*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D020032:Tyrphostins / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D053612:Janus Kinases