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Fluacrypyrim, a novel STAT3 activation inhibitor, induces cell cycle arrest and apoptosis in cancer cells harboring constitutively‐active STAT3
Author(s) -
Yu ZuYin,
Huang Rui,
Xiao He,
Sun WenFeng,
Shan YaJun,
Wang Bo,
Zhao TingTing,
Dong Bo,
Zhao ZhenHu,
Liu XiaoLan,
Wang ShengQi,
Yang RiFang,
Luo QingLiang,
Cong YuWen
Publication year - 2010
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.25169
Subject(s) - stat3 , cyclin d1 , protein tyrosine phosphatase , phosphorylation , microbiology and biotechnology , tyrosine phosphorylation , cancer research , biology , cyclin a , cell cycle checkpoint , cell growth , tyrosine kinase , signal transduction , cell cycle , apoptosis , chemistry , biochemistry
STAT3 protein has an important role in oncogenesis and is a promising anticancer target. Herein, we demonstrate that a novel small molecule fluacrypyrim (FAPM) inhibits the growth of leukemia cells by a predominant G1 arrest with significant decrease of the protein and mRNA levels of cyclin D1. As cyclin D1 is transcriptionally regulated by STAT3, FAPM is then shown to markedly inhibit the STAT3 phosphorylation with marginal effect on the other signal transducers and activators of transcription, and without effect on phosphoinositide‐3‐kinase and mitogen‐activated protein kinase pathways. Further analysis shows that FAPM significantly increases the protein tyrosine phosphatases (PTPs) activity in a dose‐dependent manner, and the inhibition of PTP activation by sodium pervanadate reverses FAPM‐induced suppression of STAT3 tyrosine phosphorylation, indicating an important role of PTP in the action of FAPM. Finally, FAPM treatment results in selective suppression of STAT3‐mediated transcriptional activity and its downstream effectors, and subsequent induction of growth arrest and apoptosis in STAT3‐dependent cancer cell lines. This study therefore identifies FAPM as a potent STAT3 activation inhibitor with possible therapeutic potential against malignancies with constitutive STAT3 activation.