Molecular disruption of oncogenic signal transducer and activator of transcription 3 (STAT3) protein

Abstract

Signal transducer and activator of transcription protein 3 (STAT3) is a latent cytosolic transcription factor that is widely recognized as being a master regulator of the cellular functions that lead to the cancer phenotype. Constitutively activated STAT3 protein activity is routinely observed in human cancers, promoting uncontrolled cell proliferation and suppressing apoptosis. Until relatively recently, inhibition of STAT3 transcriptional activity was achieved indirectly via suppression of upstream kinase activators and extracellular cytokine and (or) growth factor stimuli. However, activated STAT3 forms transcriptionally functional STAT3-STAT3 dimers, providing a valid juncture for targeted downstream molecular inhibition. STAT3's prominent role in cancer has seen a decade of innovative and novel approaches to targeting constitutively active STAT3 protein-protein complexes. This mini-review outlines the progress made towards identifying molecular agents capable of silencing aberrant STAT3 signalling through the disruption of STAT3 complexation events.

STAT3 gene polymorphisms and susceptibility to non-small cell lung cancer

“…STAT3 transcriptional factor has been found to play pivotal roles in various aspects of tumor development and progression in a number of malignancies (Darnell, 2005;Fletcher et al, 2009;Yu et al, 2009). However, there is only one article that has investigated STAT3 polymorphisms in relation to cancer risk (Vaclavicek et al, 2007).…”

“…Signal transducer and activator of transcription protein 3 (STAT3), a member of a transcription factor family that mediates various biological responses induced by cytokines and growth factors (Turkson, 2004), is implicated in cancer development and progression and has, therefore, been recognized as a type of oncogene (Darnell, 2005;Fletcher et al, 2009;Yu et al, 2009). STAT3 participates in a series of tumorigenic cellular processes such as cell proliferation, survival, apoptosis, angiogenesis, and immune responses (Karin, 2006;Grivennikov and Karin, 2010).…”

NF-κB and STAT3 – key players in liver inflammation and cancer

“…Different types of STAT3 inhibitors were designed to either directly target STAT3 by inhibiting its dimerization, DNA binding, or nuclear entry or through the targeting of upstream components in the STAT3 activation pathway [80,81]. S3I-201 is a direct STAT3 inhibitor that blocks both STAT3 dimerization and DNA-binding and transcriptional activities [82].…”

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

“…More recently, a number of promising covalent STAT3/5 SH 2 domain-binding inhibitors have been described [8,133,134,152]. These compounds exhibit potent and selective binding activity for STAT3/5 by effectively disrupting phosphopeptide interactions.…”