Fluacrypyrim, a novel STAT3 activation inhibitor, induces cell cycle arrest and apoptosis in cancer cells harboring constitutively-active STAT3.
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.
Yu
Zu-Yin
ZY
Department of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing, China.
Huang
Rui
R
Xiao
He
H
Sun
Wen-Feng
WF
Shan
Ya-Jun
YJ
Wang
Bo
B
Zhao
Ting-Ting
TT
Dong
Bo
B
Zhao
Zhen-Hu
ZH
Liu
Xiao-Lan
XL
Wang
Sheng-Qi
SQ
Yang
Ri-Fang
RF
Luo
Qing-Liang
QL
Cong
Yu-Wen
YW
D000179:Acrylates / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects*; D056741:Cyclin D / Q000235:genetics; D017931:DNA Primers; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D000179:Acrylates; D000970:Antineoplastic Agents; D056741:Cyclin D; D017931:DNA Primers; D011743:Pyrimidines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D017027:Protein Tyrosine Phosphatases; C551593:fluacrypyrim