Targeting the STAT3 signaling pathway in cancer: Role of synthetic and natural inhibitors

Abstract

Signal transducers and activators of transcription (STATs) comprise a family of cytoplasmic transcription factors that mediate intracellular signaling that is usually generated at cell surface receptors and thereby transmit it to the nucleus. Numerous studies have demonstrated constitutive activation of STAT3 in a wide variety of human tumors, including hematological malignancies (leukemias, lymphomas, and multiple myeloma) as well as diverse solid tumors (such as head and neck, breast, lung, gastric, hepatocellular, colorectal and prostate cancers). There is strong evidence to suggest that aberrant STAT3 signaling promotes initiation and progression of human cancers by either inhibiting apoptosis or inducing cell proliferation, angiogenesis, invasion, and metastasis. Suppression of STAT3 activation results in the induction of apoptosis in tumor cells, and accordingly its pharmacological modulation by tyrosine kinase inhibitors, antisense oligonucleotides, decoy nucleotides, dominant negative proteins, RNA interference and chemopreventive agents have been employed to suppress the proliferation of various human cancer cells in culture and tumorigenicity in vivo. However, the identification and development of novel drugs that can target deregulated STAT3 activation effectively remains an important scientific and clinical challenge. This review presents the evidence for critical roles of STAT3 in oncogenesis and discusses the potential for development of novel cancer therapies based on mechanistic understanding of STAT3 signaling cascade.

Two serine residues of non-metastasis protein 23-H1 are critical in inhibiting signal transducer and activator of transcription 3 activity in human lung cancer cells

“…A previous study indicated a phosphatase-stable phosphopeptide mimics target to the SH2 domain of STAT3 may inhibit the phosphorylation of STAT3 Tyr705 in cultured tumor cells (25). Drugs that control the activation of STAT3 signaling pathway, particularly in their phosphorylated state, are required for gene expression (26). In the present study, Nm23-H1, a metastasis suppressor gene, which inhibits the phosphorylation of STAT3 on Tyr705 via its Ser44 phosphorylation, provides a novel antitumor metastasis strategy in lung cancer A549 cells.…”

Immunosuppressive CD14+HLA-DRlo/negmonocytes are elevated in pancreatic cancer and “primed” by tumor-derived exosomes

“…STAT3 is a known activator of several anti-apoptotic and cell cycle progressive genes. 22 In animal models, STAT3 is a critical factor for promoting myeloid-mediated tumorigenesis. 30 Others have Exosomes isolated from two PC patient plasma samples (PC1 and PC2 Exo) and PANC-1 Exo were co-incubated with monocytes.…”

“…STAT signaling has also been implicated in the generation and proliferation of myeloid cells. 22 We therefore tested whether PC-Exo could activate this pathway by checking the phosphorylation status of STAT1 and STAT3. Through western blotting, we showed that both pSTAT1 and pSTAT3 levels were increased in the presence of both PANC-1 exosomes and exosomes isolated from PCpatient plasma.…”

Targeting Cellular Signaling Pathways in Breast Cancer Stem Cells and its Implication for Cancer Treatment

“…STAT proteins comprise a family of cytoplasm transcription factors that mediate intracellular signaling triggered by many molecules and thereby transmit it to nucleus. Among STAT proteins, STAT3 intermediates extracellular signals stimulated by cytokines, mainly IL-6, growth factors and other molecules (70). Briefly, the receptor tyrosine kinase Janus kinases (JAK) recruit STAT3, which dimerizes and is translocated to the nucleus where it recognizes specific DNA sequences and activates the transcription of target genes.…”