STAT3 and its targeting inhibitors in osteosarcoma

Abstract

Signal transducer and activator of transcription 3 (STAT3) is one of seven STAT family members involved with the regulation of cellular growth, differentiation and survival. STAT proteins are conserved among eukaryotes and are important for biological functions of embryogenesis, immunity, haematopoiesis and cell migration. STAT3 is widely expressed and located in the cytoplasm in an inactive form. STAT3 is rapidly and transiently activated by tyrosine phosphorylation by a range of signalling pathways, including cytokines from the IL-6 family and growth factors, such as EGF and PDGF. STAT3 activation and subsequent dimer formation initiates nuclear translocation of STAT3 for the regulation of target gene transcription. Four STAT3 isoforms have been identified, which have distinct biological functions. STAT3 is considered a proto-oncogene and constitutive activation of STAT3 is implicated in the development of various cancers, including multiple myeloma, leukaemia and lymphomas. In this review, we focus on recent progress on STAT3 and osteosarcoma (OS). Notably, STAT3 is overexpressed and associated with the poor prognosis of OS. Constitutive activation of STAT3 in OS appears to upregulate the expression of target oncogenes, leading to OS cell transformation, proliferation, tumour formation, invasion, metastasis, immune evasion and drug resistance. Taken together, STAT3 is a target for cancer therapy, and STAT3 inhibitors represent potential therapeutic candidates for the treatment of OS.

Keywords: STAT3 inhibitor; metastasis; oncogenes; osteosarcoma (OS); signal transducer and activator of transcription 3 (STAT3); signalling.

FIGURE 1

STAT3 secondary structure. STAT3 protein structure includes N‐terminal domain, coiled coil and DNA binding domains, a linker domain, SH2 domain involved with dimer formation and the C‐terminus. The C‐terminus of the (A) STAT3α isoform and (B) STAT3β isoform confers distinct functions of the two isoforms. STAT3, signal transducer and activator of transcription 3

FIGURE 2

STAT3α isoform tertiary structure predicted by RaptorX template‐based protein structure modelling bioinformatics analysis, http://raptorx.uchicago.edu/StructPredV2/predict/. (A) Whole sequence predicted model. (B) N‐terminal domain, aa1‐124. (C) Coiled coil, DNA binding, linker and SH2 domains, aa125‐715. (D) C‐terminal transactivation domain, aa716‐770. STAT3, signal transducer and activator of transcription 3

FIGURE 3

(A) STAT3 expression analysis performed by Genevisible®, https://genevisible.com/search. STAT3 expression analysis across 518 tissues, showing the 10 most highly expressed, including leucocyte and T‐cell populations. (B) STAT3 expression analysis across 539 cancers, showing the 10 most highly expressed, including metastatic lung, breast and adenocarcinomas. STAT3, signal transducer and activator of transcription 3

FIGURE 4

Schematic osteosarcoma cell STAT3 signalling pathways. STAT3 is activated following phosphorylation, dimer formation and nuclear translocation for the regulation of target gene transcription for processes including cellular proliferation, migration, invasion, immune evasion and drug resistance. STAT3, signal transducer and activator of transcription 3