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Mechanism of action of selective inhibitors of IL-6 induced STAT3 pathway in head and neck cancer cell lines.


ABSTRACT: Studies indicate that elevated interleukin-6 (IL-6) levels engage IL6R?-gp130 receptor complexes to activate signal transducer and activator of transcription 3 (STAT3) that is hyperactivated in many cancers including head and neck squamous cell carcinoma (HNSCC). Our previous HCS campaign identified several hits that selectively blocked IL-6-induced STAT3 activation. This study describes our investigation of the mechanism(s) of action of three of the four chemical series that progressed to lead activities: a triazolothiadiazine (864669), amino alcohol (856350), and an oxazole-piperazine (4248543). We demonstrated that all three blocked IL-6-induced upregulation of the cyclin D1 and Bcl-XL STAT3 target genes. None of the compounds exhibited direct binding interactions with STAT3 in surface plasmon resonance (SPR) binding assays; neither did they inhibit the recruitment and binding of a phospho-tyrosine-gp130 peptide to STAT3 in a fluorescence polarization assay. Furthermore, they exhibited little or no inhibition in a panel of 83 cancer-associated in vitro kinase profiling assays, including lack of inhibition of IL-6-induced Janus kinase (JAK 1, 2, and 3) activation. Further, 864669 and 4248543 selectively inhibited IL-6-induced STAT3 activation but not that induced by oncostatin M (OSM). The compounds 864669 and 4248543 abrogated IL-6-induced phosphorylation of the gp130 signaling subunit (phospho-gp130Y905) of the IL-6-receptor complex in HNSCC cell lines which generate docking sites for the SH2 domains of STAT3. Our data indicate that 864669 and 4248543 block IL-6-induced STAT activation by interfering with the recruitment, assembly, or activation of the hexamer-activated IL-6/IL-6R?/gp130 signaling complex that occurs after IL-6 binding to IL-6R? subunits.

SUBMITTER: Sen M 

PROVIDER: S-EPMC5480263 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Mechanism of action of selective inhibitors of IL-6 induced STAT3 pathway in head and neck cancer cell lines.

Sen Malabika M   Johnston Paul A PA   Pollock Netanya I NI   DeGrave Kara K   Joyce Sonali C SC   Freilino Maria L ML   Hua Yun Y   Camarco Daniel P DP   Close David A DA   Huryn Donna M DM   Wipf Peter P   Grandis Jennifer R JR  

Journal of chemical biology 20170511 3


Studies indicate that elevated interleukin-6 (IL-6) levels engage IL6Rα-gp130 receptor complexes to activate signal transducer and activator of transcription 3 (STAT3) that is hyperactivated in many cancers including head and neck squamous cell carcinoma (HNSCC). Our previous HCS campaign identified several hits that selectively blocked IL-6-induced STAT3 activation. This study describes our investigation of the mechanism(s) of action of three of the four chemical series that progressed to lead  ...[more]

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2021-06-16 | GSE178222 | GEO