STAT3 Inhibitors: A Novel Insight for Anticancer Therapy of Pancreatic Cancer

Abstract

The signal transducer and activator of transcription (STAT) is a family of intracellular cytoplasmic transcription factors involved in many biological functions in mammalian signal transduction. Among them, STAT3 is involved in cell proliferation, differentiation, apoptosis, and inflammatory responses. Despite the advances in the treatment of pancreatic cancer in the past decade, the prognosis for patients with pancreatic cancer remains poor. STAT3 has been shown to play a pro-cancer role in a variety of cancers, and inhibitors of STAT3 are used in pre-clinical and clinical studies. We reviewed the relationship between STAT3 and pancreatic cancer and the latest results on the use of STAT3 inhibitors in pancreatic cancer, with the aim of providing insights and ideas around STAT3 inhibitors for a new generation of chemotherapeutic modalities for pancreatic cancer.

Keywords: STAT3; drug therapy; molecular targeted therapy; pancreatic cancer.

Figure 1

The three-dimensional structure and linear structure of STAT3. (A) The protein primary structure of STAT3; (B) the protein secondary structure of STAT3; (C) the linear structure of STAT3, including six structural domains, N-terminal domain (NTD), coiled-coil domain (CCD), DNA-binding domain (DBD), linking domain (LD), SH2 domain and transcriptional activation domain (TAD). STAT3 structure was retrieved from PDB database (PDB ID: 6QHD), then visualized with PyMol software.

Figure 2

IL-6/JAK/STAT3 signaling pathway. IL-6 binds to the IL-6 receptor α (IL-6Rα), thereby inducing the formation of a complex consisting of two molecules each of IL-6, IL-6R, and GP130. Formation of this complex leads to activation of the JAK/STAT3 signaling pathway, resulting in the transcription of STAT3 target genes. Some growth factors can also activate the JAK/STAT3 pathway. Soluble IL-6R (sIL-6R) can be generated by alternative splicing of IL6R mRNA. sIL-6R binds to IL-6 to form a complex that binds and induces dimerization of GP130, leading to activation of downstream signaling pathways. Once bound to gp130, STAT3 is phosphorylated by JAK at tyrosine 705, leading to STAT3 dimerization and nuclear translocation, followed by STAT3-mediated transcription of target genes. Some molecules, such as miR-181d, miR-124, miR-451a, miR-551-3p, and tyrosine phosphatase can inhibit the STAT3 pathway. MiR-211, miR-222, miR-147, and miR-30 can promote STAT3 gene expression. When STAT3 is activated, it can promote the function of downstream molecules. Abbreviations: miR, microRNA; EGFR, epidermal growth factor receptor; CTGFR, connective tissue growth factor receptor; PDGFR, platelet-derived growth factor receptor.