» Articles » PMID: 23322008

A Novel Inhibitor of STAT3 Homodimerization Selectively Suppresses STAT3 Activity and Malignant Transformation

Overview
Journal Cancer Res
Specialty Oncology
Date 2013 Jan 17
PMID 23322008
Citations 76
Authors
Affiliations
Soon will be listed here.
Abstract

STAT3-STAT3 dimerization, which involves reciprocal binding of the STAT3-SH2 domain to phosphorylated tyrosine-705 (Y-705), is required for STAT3 nuclear translocation, DNA binding, and transcriptional regulation of downstream target genes. Here, we describe a small molecule S3I-1757 capable of disrupting STAT3-STAT3 dimerization, activation, and malignant transforming activity. Fluorescence polarization assay and molecular modeling suggest that S3I-1757 interacts with the phospho-Y-705-binding site in the SH2 domain and displaces fluorescein-labeled GpYLPQTV phosphotyrosine peptide from binding to STAT3. We generated hemagglutinin (HA)-tagged STAT3 and FLAG-tagged STAT3 and showed using coimmunoprecipitation and colocalization studies that S3I-1757 inhibits STAT3 dimerization and STAT3-EGF receptor (EGFR) binding in intact cells. Treatment of human cancer cells with S3I-1757 (but not a closely related analog, S3I-1756, which does not inhibit STAT3 dimerization), inhibits selectively the phosphorylation of STAT3 over AKT1 and ERK1/2 (MAPK3/1), nuclear accumulation of P-Y705-STAT3, STAT3-DNA binding, and transcriptional activation and suppresses the expression levels of STAT3 target genes, such as Bcl-xL (BCL2L1), survivin (BIRC5), cyclin D1 (CCND1), and matrix metalloproteinase (MMP)-9. Furthermore, S3I-1757, but not S3I-1756, inhibits anchorage-dependent and -independent growth, migration, and invasion of human cancer cells, which depend on STAT3. Finally, STAT3-C, a genetically engineered mutant of STAT3 that forms a constitutively dimerized STAT3, rescues cells from the effects of S3I-1757 inhibition. Thus, we have developed S3I-1757 as a STAT3-STAT3 dimerization inhibitor capable of blocking hyperactivated STAT3 and suppressing malignant transformation in human cancer cells that depend on STAT3.

Citing Articles

Unraveling Stereochemical Structure-Activity Relationships of Sesquiterpene Lactones for Inhibitory Effects on STAT3 Activation.

An S, Chun J, Lee J, Kim Y, Noh M, Ko H Biomol Ther (Seoul). 2024; 32(5):627-634.

PMID: 39091020 PMC: 11392665. DOI: 10.4062/biomolther.2023.210.


Signaling pathways in liver cancer: pathogenesis and targeted therapy.

Xue Y, Ruan Y, Wang Y, Xiao P, Xu J Mol Biomed. 2024; 5(1):20.

PMID: 38816668 PMC: 11139849. DOI: 10.1186/s43556-024-00184-0.


Unraveling the complexity of STAT3 in cancer: molecular understanding and drug discovery.

Hu Y, Dong Z, Liu K J Exp Clin Cancer Res. 2024; 43(1):23.

PMID: 38245798 PMC: 10799433. DOI: 10.1186/s13046-024-02949-5.


METTL3 promotes colorectal cancer progression through activating JAK1/STAT3 signaling pathway.

Sun Y, Gong W, Zhang S Cell Death Dis. 2023; 14(11):765.

PMID: 38001065 PMC: 10673931. DOI: 10.1038/s41419-023-06287-w.


Targeting of STAT5 using the small molecule topotecan hydrochloride suppresses acute myeloid leukemia progression.

Li J, Tang B, Miao Y, Li G, Sun Z Oncol Rep. 2023; 50(6).

PMID: 37830151 PMC: 10603551. DOI: 10.3892/or.2023.8645.


References
1.
Caldenhoven E, van Dijk T, Solari R, Armstrong J, Raaijmakers J, Lammers J . STAT3beta, a splice variant of transcription factor STAT3, is a dominant negative regulator of transcription. J Biol Chem. 1996; 271(22):13221-7. DOI: 10.1074/jbc.271.22.13221. View

2.
Shao H, Cheng H, Cook R, Tweardy D . Identification and characterization of signal transducer and activator of transcription 3 recruitment sites within the epidermal growth factor receptor. Cancer Res. 2003; 63(14):3923-30. View

3.
Urlam M, Pireddu R, Ge Y, Zhang X, Sun Y, Lawrence H . Development of new -Arylbenzamides as STAT3 Dimerization Inhibitors. Medchemcomm. 2013; 4(6):932-941. PMC: 3780559. DOI: 10.1039/C3MD20323A. View

4.
Yu C, Meyer D, Campbell G, Larner A, Schwartz J, Jove R . Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein. Science. 1995; 269(5220):81-3. DOI: 10.1126/science.7541555. View

5.
Mandal P, Gao F, Lu Z, Ren Z, Ramesh R, Birtwistle J . Potent and selective phosphopeptide mimetic prodrugs targeted to the Src homology 2 (SH2) domain of signal transducer and activator of transcription 3. J Med Chem. 2011; 54(10):3549-63. PMC: 3319156. DOI: 10.1021/jm2000882. View