STAT3 pathway in cancers: Past, present, and future

Abstract

Signal transducer and activator of transcription 3 (STAT3), a member of the STAT family, discovered in the cytoplasm of almost all types of mammalian cells, plays a significant role in biological functions. The duration of STAT3 activation in normal tissues is a transient event and is strictly regulated. However, in cancer tissues, STAT3 is activated in an aberrant manner and is induced by certain cytokines. The continuous activation of STAT3 regulates the expression of downstream proteins associated with the formation, progression, and metastasis of cancers. Thus, elucidating the mechanisms of STAT3 regulation and designing inhibitors targeting the STAT3 pathway are considered promising strategies for cancer treatment. This review aims to introduce the history, research advances, and prospects concerning the STAT3 pathway in cancer. We review the mechanisms of STAT3 pathway regulation and the consequent cancer hallmarks associated with tumor biology that are induced by the STAT3 pathway. Moreover, we summarize the emerging development of inhibitors that target the STAT3 pathway and novel drug delivery systems for delivering these inhibitors. The barriers against targeting the STAT3 pathway, the focus of future research on promising targets in the STAT3 pathway, and our perspective on the overall utility of STAT3 pathway inhibitors in cancer treatment are also discussed.

Keywords: STAT3; STAT3 pathway inhibitors; cancer hallmarks; cancer treatment.

FIGURE 1

Brief history of signal transducer and activator of transcription 3 (STAT3) studies

FIGURE 2

(A, B) Schematic and functional architecture of STAT3 protein. STAT3 has the construction, including N‐terminus domain, coiled‐coil domain, DNA‐binding domain, linker, SRC homology 2 and C‐terminus domain. Each of them plays a role such as DNA binding, dimerization, and transactivation. Reprinted with permission from Mertens et al. Copyright 2015 by National Academy of Sciences

FIGURE 3

Schematic of pathways activating STAT3 signaling. Once cytokines and growth factors such as interleukin‐6 (IL‐6), epidermal growth factor (EGF) and G‐proteins as positive regulators bind to their receptors, ligand‐bound receptors undergo conformational changes and activate Janus kinase (JAK) family. STAT3 molecules are phosphorylated on Y705 by intracellular non‐receptor tyrosine kinases (RTKs) such as JAK and RTKs such as EGF receptor, or STAT3 can also be activated directly by Src and Abl. While PTP, suppressor of cytokine signaling and protein inhibitor of activated STAT as the negative regulators can inhibit the activity of STAT3. The dimerization of two activated STAT3 molecules binding via SH2 domain enters the nucleus and then binds to target gene

FIGURE 4

Schematic of the relationship between STAT3 and cancer hallmarks. STAT3 improve the representation of tumor hallmarks through the following five aspects: inflammatory microenvironment and immunosuppression; cell proliferation and apoptosis; epithelial‐mesenchymal transition and cancer stem‐like cells; deregulation of the cellular energetics; angiogenesis and invasion and metastasis

FIGURE 5

Schematic of STAT3 signaling in tumor microenvironment (TME). STAT3 activation has the ability in affecting TME via up‐ or downregulating downstream molecules and promoting tumor cell proliferation and survival, angiogenesis, immune evasion as the result. The functions of natural killer cell and dendritic cell in antigen presentation and target cell recognition are inhibited. While macrophage polarization toward M2‐like endotype and the immune checkpoint expression and proliferation of myeloid‐derived suppressor cell, cancer‐associated fibroblasts, and regulatory T‐cell are promoted by phosphorylated STAT3

FIGURE 6

Schematic of STAT3 signaling inhibitors. The principle of STAT3 inhibitors in tumor treatment is based on targeting upstream proteins of the STAT3 signaling or directly targeting STAT3; inhibition of upstream cytokine such as IL‐6 and tyrosine kinases JAK with small‐molecule inhibitors and natural compound such as tocilizumab, siltuximab, curcumin, ruxolitinib. As for inhibiting STAT3 in direct way, NH2‐terminal, DNA‐binding and SH2 domains can be targeted with OPB‐51602, S3I‐201, STAT3 decoy, G‐quartet oligodeoxynucleotide, AZD9150. Negative regulators of STAT3 can also play a role as STAT3 inhibitors (Figure 3)