Dietary compounds as potent inhibitors of the signal transducers and activators of transcription (STAT) 3 regulatory network

Abstract

Signal transducers and activators of transcription (STAT) proteins were described as a family of latent cytosolic transcription factors whose activation is dependent on phosphorylation via growth factor- and cytokine-membrane receptors including interferon and interleukin, or by non-receptor intracellular tyrosine kinases, including Src. A vast majority of natural substances are capable of modulating mitogenic signals, cell survival, apoptosis, cell cycle regulation, angiogenesis as well as processes involved in metastasis development. The inhibition of STAT3 phosphorylation by natural and dietary compounds leads to decreased protein expression of STAT3 targets essentially involved in regulation of the cell cycle and apoptotic cell death. This review details the cell signaling pathways involving STAT transcription factors as well as the corresponding compounds from nature able to interfere with this regulatory system in human cancer.

Fig. 1

a Schematic representation of the structural domains of STAT proteins, adapted from (Liu et al. 2002). The STAT protein contains an N-terminal domain (ND) responsible for stabilizing the binding of STAT dimers to DNA. The “coiled-coil” domain (CCD) is involved in interactions with other proteins. The DNA binding domain (DBD) allows physical contact with the STAT response elements in the promoter of target genes. The linker domain connects the DBD to the “Src homology 2” domain (SH2) and is important in the dimerization of STAT proteins. A tyrosine residue (Y) in the TAD domain is phosphorylated and interacts with the SH2 domain of another monomer. The C-terminal TAD area is responsible for the transcriptional activation of target genes. Areas in purple represent the different sites of action of specific inhibitors of STAT3 that have been recently identified. b Schematic representation of the structural domains of JAK proteins, adapted from Braunstein et al. (2003). The N-terminal region of the JAK protein contains the JH3–JH7 domains (shown in purple) that are involved in protein binding with the receptor. Next, the JH2 domain (shown in blue) corresponds to the domain pseudokinase necessary to regulate the catalytic activity of JH1. The JH1 domain is found in the C-terminal and contains the kinase activity. This domain contains two tyrosines that play an important role in protein kinase activity

Fig. 2

The JAK/STAT signaling pathway. Ligand binding to the membrane receptor leads to receptor dimerization (1) and activation of associated JAK proteins (2). JAK phosphorylates the receptor (3) to recruit and phosphorylate cytoplasmic STAT factors (4). Phosphorylation of STAT factors leading to their dimerization (5). As a dimer, STAT will be translocated into the nucleus (6) to specifically bind to DNA at the GAS (IFN-gamma-activated site). The STATE dimer activates the transcription of its target genes (7). This figure presents STAT3 and its target genes in the nucleus as an example

Fig. 3

Chemical structures of different dietary STAT3 inhibitors

Fig. 4

JAK/STAT signaling pathway targeted by different inhibitors. These inhibitors target the following points in the JAK/STAT signaling pathway: constitutive activation of JAK2, STAT3 phosphorylation, formation of the STAT dimer and binding activity of STAT3 to DNA. In contrast, the phosphatase SHP-1 can be activated