Inhibition of STAT3 expression/activity could be a good strategy to modulate tumor cell survival and responses to cancer chemotherapeutics or immune cytotoxicity.
CXCR4 contributes to tumor angiogenesis in gastric cancer by inducing STAT3-dependent VEGF expression and represents a promising therapeutic target for this malignancy.
Constitutive activation of signal transducer and activator of transcription 3 (STAT3) occurs in ∼70% of human cancers, and STAT3 is regarded as one of the most promising targets for cancer therapy.
Therefore, elucidating the regulatory mechanism of these signaling steps of unphosphorylated STAT3 is a potential step in the discovery of a novel cancer drug.
This article reviews several approaches that have been pursued for targeting Stat3 in cancer therapy including antisense strategies, tyrosine kinase inhibition, decoy phosphopeptides, decoy duplex oligonucleotides and G-quartet oligodeoxynucleotides (GQ-ODN).
Signal transducer and activator of transcription 3 (STAT3), a previously accepted tumor-promoting protein in various malignancies, plays a key role in the process of cancer glycolysis.
Thus, together our result demonstrates that DX10 may be used in combination therapy with STAT3 inhibitor like WP for combating cancer with constitutively active STAT3.
In this review, we will: (a) explain the mechanisms of STAT activation in normal and malignant signaling; (b) summarize recent evidence for the critical role of constitutively activated Stat3 and Stat5 in oncogenesis; (c) identify candidate STAT target genes implicated in tumor progression; and (d) discuss molecular and pharmacological strategies to interfere with STAT signaling for potential therapeutic intervention in human cancer.
Large-scale screening of cancer cell lines with a JAK2 inhibitor that blocks STAT3 function revealed a more than 30-fold range in sensitivity in PDAC, and showed a close correlation of sensitivity with levels of tyrosine-phosphorylated STAT3 and of the gp130 receptor, an upstream signaling component.
Correlation of expression levels of these markers in the oral cancer cohort of The Cancer Genome Atlas (n = 313) with treatment outcome identified 54 genes (p < 0.05 or fold change >2) associated with disease recurrence, 8 genes (NQO1, UBE2C, EDNRB, FKBP4, STAT3, HOXA1, RIT1, AURKA) being significant with high fold change.
This resulted in the suppression of STAT3 target gene expression, in the inhibition of migration and proliferation, and in the induction of apoptosis at low concentrations [half maximal effective concentration (EC(50)), <3 micromol/L]. rPP-C8 did not affect normal fibroblasts and represents an interesting lead for the development of novel cancer drugs targeting the coiled-coil domain of STAT3.
Numerous prior studies on fighting cancer have been based on using inhibitors of JAK-STAT pathway (signal transducer and activator of transcription 3 (STAT3) inhibitor in particular), a signaling pathway responsible for progression of many types of cancer cells.
Moreover, we showed that the epigenetic rebalance between decreased BCR-ABL/STAT5/c-Myc and enhanced STAT3/multi-drug resistance (MDR) pathways is characteristic of the cancer stem cell-like property of K562/ADR.
Depression induces secretion of neuropeptide Y from prostate cancer cells, which, in turn, recruits myeloid-derived suppressor cells (MDSC) to the tumor; tumor cells and MDSCs secrete IL6, which activates STAT3 within cancer cells.
It will be of interest to follow up CD patients carrying either JAK2 or STAT3 risk alleles for development of further secondary effects, including cancer.
Furthermore, previous studies have reported that IL-6-STAT3 pathway is overexpressed in various types of cancer and contributes to cell proliferation, apoptosis, invasion/migration, chemoresistance and modulation of stemness features.
Gankyrin deficiency in non-parenchymal cells, but not in parenchymal cells, reduced STAT3 activity, interleukin (IL)-6 production, and cancer stem cell marker (Bmi1 and epithelial cell adhesion molecule [EpCAM]) expression, leading to attenuated tumorigenic potential.
To further address the role of Stat3 in skin SCC tumorigenesis, we have analyzed a panel of human skin-derived cell lines ranging from normal human epidermal keratinocytes (NHEK), to non-tumorigenic transformed skin cells (HaCaT), to highly tumorigenic cells (SRB1-m7 and SRB12-p9) and observed a positive correlation between Stat3 phosphorylation and SCC malignancy.