Abstract
Signal transducer and activator of transcription 3 (STAT3) plays a critical role in promoting the proliferation and survival of tumor cells. As a ubiquitously-expressed transcription factor, STAT3 has commonly been considered an “undruggable” target for therapy; thus, much research has focused on targeting upstream pathways to reduce the expression or phosphorylation/activation of STAT3 in tumor cells. Recently, however, novel approaches have been developed to directly inhibit STAT3 in human cancers, in the hope of reducing the survival and proliferation of tumor cells. Several of these agents are nucleic acid-based, including the antisense molecule AZD9150, CpG-coupled STAT3 siRNA, G-quartet oligodeoxynucleotides (GQ-ODNs), and STAT3 decoys. While the AZD9150 and CpG-STAT3 siRNA interfere with STAT3 expression, STAT3 decoys and GQ-ODNs target constitutively activated STAT3 and modulate its ability to bind to target genes. Both STAT3 decoy and AZD9150 have advanced to clinical testing in humans. Here we will review the current understanding of the structures, mechanisms, and potential clinical utilities of the nucleic acid-based STAT3 inhibitors.
Highlights
Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is overexpressed and/or hyperactivated in multiple human cancers, where it enhances tumor cell survival and invasion through transcription of anti-apoptotic and pro-proliferative genes [1]
STAT3 activation in tumor cells leads to increased production of immunosuppressive cytokines, including interleukin-6 (IL-6), IL-10, vascular endothelial growth factor (VEGF), and transforming growth factor-b1 (TGF-β1) [14,15,16,17]
Cytokines and growth factors produced by tumor cells commonly lead to STAT3 activation in tumor-infiltrating immune cells
Summary
Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is overexpressed and/or hyperactivated in multiple human cancers, where it enhances tumor cell survival and invasion through transcription of anti-apoptotic and pro-proliferative genes [1]. STAT3 activation in tumor cells leads to increased production of immunosuppressive cytokines, including interleukin-6 (IL-6), IL-10, vascular endothelial growth factor (VEGF), and transforming growth factor-b1 (TGF-β1) [14,15,16,17]. Ligand binding initiates engagement of receptor tyrosine kinases, such as the receptors for epidermal growth factor (EGF) or vascular endothelial growth factor (VEGF), or receptors that lack intrinsic tyrosine kinase activity, such as the IL-6 receptor/gp130 complex, and/or nonreceptor tyrosine kinases such as c-Src [19]. Ligand binding cytoplasmic regions ofofreceptor tyrosine kinases aresuch subjected autophosphorylation, thesefactor sites initiates engagement receptor tyrosine kinases, as thetoreceptors for epidermaland growth of phosphorylation serve growth to recruit. Vascular endothelial factor (VEGF), that phosphorylated/activated lack intrinsic tyrosine kinase the activated receptor.
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