The Dose Dependent Effects of Ruxolitinib on the Invasion and Tumorigenesis in Gliomas Cells via Inhibition of Interferon Gamma-Depended JAK/STAT Signaling Pathway

Abstract

Objective : Glioblastoma multiforme (GBM) is the most aggressive for of brain tumor and treatment often fails due to the invasion of tumor cells into neighboring healthy brain tissues. Activation of the Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling pathway is essential for normal cellular function including angiogenesis, and has been proposed to have a pivotal role in glioma invasion. This study aimed to determine the dose-dependent effects of ruxolitinib, an inhibitor of JAK, on the interferon (IFN)-I/IFN-α/IFN-β receptor/STAT and IFN-γ/IFN-γ receptor/STAT1 axes of the IFN-receptor-dependent JAK/STAT signaling pathway in glioblastoma invasion and tumorigenesis in U87 glioblastoma tumor spheroids. Methods : We administered three different doses of ruxolitinib (50, 100, and 200 nM) to human U87 glioblastoma spheroids and analyzed the gene expression profiles of IFNs receptors from the JAK/STAT pathway. To evaluate activation of this pathway, we quantified the phosphorylation of JAK and STAT proteins using Western blotting. Results : Quantitative real-time polymerase chain reaction analysis demonstrated that ruxolitinib led to upregulated of the IFN-α and IFN-γ while no change on the hypoxia-inducible factor-1α and vascular endothelial growth factor expression levels. Additionally, we showed that ruxolitinib inhibited phosphorylation of JAK/STAT proteins. The inhibition of IFNs dependent JAK/STAT signaling by ruxolitinib leads to decreases of the U87 cells invasiveness and tumorigenesis. We demonstrate that ruxolitinib may inhibit glioma invasion and tumorigenesis through inhibition of the IFN-induced JAK/STAT signaling pathway. Conclusion : Collectively, our results revealed that ruxolitinib may have therapeutic potential in glioblastomas, possibly by JAK/ STAT signaling triggered by IFN-α and IFN-γ.

Prognostic value and immune relevancy of a combined autophagy-, apoptosis- and necrosis-related gene signature in glioblastoma

“…In the case of the high CDI group, ruxolitinib was uncovered as one of the candidate drugs. Ruxolitinib was recently found to prevent glioblastoma invasion and tumorigenesis by inhibiting the IFN-induced JAK/STAT signaling pathway [ 94 , 95 ]. Besides, it has also been proposed for use in patients with chronic neutrophilic leukemia for its safety and efficacy in inhibiting JAK1/2 [ 96 ].…”

Pyrazole-containing pharmaceuticals: target, pharmacological activity, and their SAR studies

“…The Janus kinase (JAK) family of protein tyrosine kinases includes JAK1, JAK2, JAK3, and non-receptor tyrosine kinase 2 (TYK2). 65 JAKs play a key role in intracellular signaling pathways for various cytokines and growth factors essential for hematopoiesis, such as interleukins, erythropoietin, and thrombopoietin. 66 JAKs have multiple functions: JAK1 and JAK3 promote lymphocyte differentiation, survival, and function, while JAK2 promotes signaling of erythropoietin and thrombopoietin.…”

“…147 In 2019, Liu's group noted that axitinib (64) could fit well into the DFG-in conformation, 148 with the indazole part forming two hydrogen bonds with Cys673 and Glu671 in the hinge-binding region, allowing for tighter binding to the VEGFR receptor. Pazopanib (65), also a small molecule inhibitor of multiple protein tyrosine kinases, was approved by the FDA in 2009 for the treatment of advanced renal cell carcinoma and advanced soft tissue sarcoma in patients on prior chemotherapy (Fig. 39).…”

Targeting protein kinases for anti-glioma treatment

“…Currently ruxolitinib combined with temozolomide and radiation therapy is investigated for Grade III gliomas and glioblastoma (NCT03514069). Preclinical research showed that treatment with ruxolitinib decreased the U87 malignant glioma cells invasiveness and tumorigenesis [33].…”