The potential and controversy of targeting STAT family members in cancer

Current treatment strategies for inflammatory bowel diseases (IBDs) are associated with a lower efficacy and with several side effects that strongly affect the quality of life of IBD patients. Consequently, the development of new therapies, combining efficacy and safety is an important goal in the field of intestinal inflammation. In this context, evidence supports that polyphenols can be promising candidates due to their ability to modulate intracellular inflammatory signalling cascades. Luteolin, a naturally occurring flavonoid, exhibits anti-inflammatory properties in several models of inflammation. However, its action against intestinal inflammation has been poorly explored. Therefore, there is a lack of scientific knowledge about the potential impact of luteolin in the intestinal inflammation, particularly regarding the underlying molecular mechanisms by which luteolin can exert its anti-inflammatory action. We assessed the potential anti-inflammatory effect of luteolin in a cellular model of intestinal inflammation using cytokine-stimulated HT-29 colon epithelial cells, and the underlying key molecular mechanisms were identified. Luteolin significantly inhibited interleukine-8 (IL-8) production, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression and nitric oxide (˙NO) overproduction induced by cytokines, indicating that luteolin negatively modulates key inflammatory signalling cascades underlying intestinal inflammation. Mechanistically, the inhibition of the JAK/STAT pathway was identified as a critical mechanism by which luteolin exerts its intestinal anti-inflammatory action. This study uncovers novel molecular mechanisms by which luteolin may act against intestinal inflammation, which might support the use of luteolin as a future therapeutic strategy in IBD.

Luteolin suppresses the JAK/STAT pathway in a cellular model of intestinal inflammation

Cytotoxicity of apigenin toward multiple myeloma cell lines and suppression of iNOS and COX-2 expression in STAT1-transfected HEK293 cells.

Osteoarthritis (OA) is an age-related chronic progressive degenerative disease that induces persistent pain and disabilities. The development of OA is a complex process, and the risk factors are various, including aging, genetics, trauma and altered biomechanics. Inflammation and immunity play an important role in the pathogenesis of OA. JAK/STAT pathway is one of the most prominent intracellular signaling pathways, regulating cell proliferation, differentiation, and apoptosis. Inflammatory factors can act as the initiators of JAK/STAT pathway, which is implicated in the pathophysiological activity of chondrocyte. In this article, we provide a review on the importance of JAK/STAT pathway in the pathological development of OA. Potentially, JAK/STAT pathway becomes a therapeutic target for managing OA. 

https://www.frontiersin.org/articles/10.3389/fendo.2022.1069057/pdf

The potential roles of JAK/STAT signaling in the progression of osteoarthritis

Epithelial-to-mesenchymal transition hinders interferon-γ-dependent immunosurveillance in lung cancer cells.

Interferons (IFNs) have potent anti-proliferative, pro-apoptotic, and immunomodulatory activities against cancer. However, the clinical utility of IFNs is limited by toxicity and pharmacokinetics making it difficult to achieve sustained therapeutic levels especially in solid tumors. Signal Transducer and Activator of Transcription 1 (STAT1) or a modified STAT1 (designated STAT1-CC) that is hyper-responsive to IFN were overexpressed in lung cancer SPC-A-1 and H1299 cells using lentiviral vectors. Transduction efficiency was monitored using enhanced green fluorescent protein (EGFP) expression. After transduction, cells were treated with interferon-gamma (IFN-γ) or interferon-beta (IFN-β) and monitored for cell proliferation, migration, and invasiveness using Cell Counting Kit-8 and transwell chamber assays and for apoptosis using Annexin V detection by flow cytometry. In addition, levels of STAT1, STAT1 Tyr-701 phosphorylation (pSTAT1), fibronectin, and β-catenin were determined using western blotting. In the case of IFN-γ stimulation, levels of S100A4, proliferating cell nuclear antigen (PCNA), and c-fos expression were also determined. We found that expression of STAT1 or STAT1-CC enhanced the effect of IFN-γ and, IFN-β on inhibition of human lung cancer cell proliferation, migration and invasiveness. Moreover, STAT1 and STAT1-CC expression caused increases in pSTAT1 and decreases in fibronectin and β-catenin levels. STAT1-CC showed increased effects compared to STAT1 on IFN-γ induced pSTAT1 and down-regulation of S100A4, PCNA, and c-fos levels. The results show that STAT1-CC exhibited more strength in improving the antitumor response of IFNs in lung cancer cells. Results from this study suggest that combined treatment of IFNs and STAT1-CC might be a feasible approach for the clinical management of lung cancer in the future.

/pdf/stat1-modification-improves-therapeutic-effects-of-3udmqq82oe.pdf

STAT1 modification improves therapeutic effects of interferons on lung cancer cells

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STAT1 modification improves therapeutic effects of interferons on lung cancer cells