STAT3/5 Inhibitors Suppress Proliferation in Bladder Cancer and Enhance Oncolytic Adenovirus Therapy

Abstract

The JAK-STAT signalling pathway regulates cellular processes like cell division, cell death and immune regulation. Dysregulation has been identified in solid tumours and STAT3 activation is a marker for poor outcome. The aim of this study was to explore potential therapeutic strategies by targeting this pathway in bladder cancer (BC). High STAT3 expression was detected in 51.3% from 149 patient specimens with invasive bladder cancer by immunohistochemistry. Protein expression of JAK, STAT and downstream targets were confirmed in 10 cell lines. Effects of the JAK inhibitors Ruxolitinib and BSK-805, and STAT3/5 inhibitors Stattic, Nifuroxazide and SH-4-54 were analysed by cell viability assays, immunoblotting, apoptosis and cell cycle progression. Treatment with STAT3/5 but not JAK1/2 inhibitors reduced survival, levels of phosphorylated STAT3 and Cyclin-D1 and increased apoptosis. Tumour xenografts, using the chicken chorioallantoic membrane (CAM) model responded to Stattic monotherapy. Combination of Stattic with Cisplatin, Docetaxel, Gemcitabine, Paclitaxel and CDK4/6 inhibitors showed additive effects. The combination of Stattic with the oncolytic adenovirus XVir-N-31 increased viral replication and cell lysis. Our results provide evidence that inhibitors against STAT3/5 are promising as novel mono- and combination therapy in bladder cancer.

BCL2L15 Depletion Inhibits Endometrial Receptivity via the STAT1 Signaling Pathway

“…Consistent with the literature, our results found that shBCL2L15 EEC proliferation was inhibited by fludarabine treatment. However, Stattic induced significant apoptosis at 24 h in shBCL2L15; these results reflect those of Sruthi et al, who also found that Stattic induced bladder cancer cell apoptosis at 24 h by arresting the G2/M cell cycle [44]. Blocking the STAT1 pathway with fludarabine increased the expression of genes promoting conceptus elongation, endometrial receptivity markers, cell adhesion molecules, and PGR, except for ITGB3.…”

Integrative Analysis the characterization of peroxiredoxins in pan-cancer

“…To investigate how PRDX6 regulated cell proliferation signaling, the GSEA analysis and found JAK-STAT3 pathway was significantly enriched in PRDX high group (Figure 6E, Figure 8A). STAT3 plays as an important role in urological related tumors 34 , and previous study has confirmed that STAT3 as the upstream signaling of CDK4/6 pathway 35 . Taken together, we speculated that JAK-STAT3 signaling can be regulated by PRDX6 to impact the proliferation of BLCA cells.…”

Oncolytic Virotherapy in Solid Tumors: The Challenges and Achievements

“…IFN-I activates the protein kinase RNA-activated (PKR) signaling pathway leading to protein synthesis blockade and viral clearance [ 98 ]. Tumor cells have defects in antiviral pathways such as IFN-I, PKR, and JAK-STAT, resulting in the survival and proliferation of OVs, specifically in tumor cells [ 99 , 100 , 101 ]. Lysis of OV-infected cells releases a very diverse TAAs that prime immune cells to induce a local and systemic vaccination against the released TAAs [ 92 ].…”