STAT3 signaling: anticancer strategies and challenges

Abstract

Multiple lines of evidence place STAT3 at a central node in the development, progression, and maintenance of many human tumors, and STAT3 has been validated as an anti-cancer target in several contexts. STAT3 modulates the transcription of a variety of genes involved in the regulation of critical functions, including cell differentiation, proliferation, apoptosis, angiogenesis, metastasis, and immune responses. For many cancers, elevated levels of activated STAT3 have been associated with a poor prognosis. We review approaches that have been pursued to target STAT3, and we highlight some of the promises and challenges associated with developing an anticancer drug that might therapeutically inhibit the STAT3 signaling pathway.

Figure 1. Receptor activation by growth factors (purple) and cytokines (orange) leading to STAT3 activation and nuclear translocation

In the canonical STAT3 signaling pathway, activation of cell surface growth factor and cytokine receptors induces specific tyrosine phosphorylation (small red circles) of receptor chains to create docking sites for the recruitment of latent cytoplasmic STAT3 (dark gray geometries), which contain SH-2 domains (shown as indentations) that recognize sites of tyrosine phosphorylation. After the recruitment of STAT3 to activated receptors, STAT3 becomes activated by phosphorylation (at Y⁷⁰⁵; see text for details). Phosphorylation of STAT3 can be catalyzed by the intrinsic tyrosine kinase activity of the activated growth factor receptor (green elongated ovals) or by the Janus kinase (JAK) that associates with activated cytokine receptors (blue elongated ovals). Phosphorylated STAT3 homodimerizes, via reciprocal intermolecular interactions between SH-2 domains and phosphorylation sites, and dimers translocate into the nucleus. Passage of dimers through the nuclear pore complex (red rings) is facilitated through interactions with importin α5, importin α7, and importin β; nuclear import of nonphosphorylated STAT3 may also occur by importin α3 (not shown). In the nucleus, STAT3 dimers bind to promoter elements of responsive target genes to regulate their transcription. See Tables 1 and 2 for specific activators and targets of STAT3 activity.

Figure 2. Phosphorylation (i.e., activation) of STAT3 as a function of translocation between nucleus and cytoplasm

The translocation of STAT3 across the nuclear membrane represents one target of intervention in the STAT3 signaling pathway. Inhibition of exportin-1 (i.e., the ortholog of yeast Crm1) by the fungal toxin Leptomycin B, for example, results in nuclear retention of STAT3, where phosphotyrosine phosphatase activities (e.g., TC45) inactivate STAT3 and preclude its function as a transcription factor. The effects of importin inhibitors upon STAT3 function are not yet defined. (See text for details.)