Interactions between Pro-inflammatory Cytokines and Estrogen Receptors in Endometrial Cancer

Endometrial cancer (EC) is a hormone-driven malignancy in which estrogen receptor (ER) signaling plays a central role. Meanwhile, chronic inflammation, particularly mediated by pro-inflammatory cytokines such as interleukin-6 (IL-6) and interleukin-17 (IL-17), has emerged as a key contributor to endometrial cancer progression. This review examines the interplay between IL-6, IL-17, and estrogen receptors (ERα and ERβ) in endometrial cancer cells, highlighting how these cytokines regulate ER expression and function through multiple signaling pathways, including the Janus kinase/signal transducer and activator of transcription (JAK/STAT), nuclear factor-κB (NF-κB), and mitogen-activated protein kinase (MAPK) pathways. IL-6 and IL-17 have been shown to upregulate ERα and suppress ERβ, thereby enhancing estrogen-mediated tumor proliferation and potentially contributing to hormonal therapy resistance. Moreover, evidence suggests a bidirectional feedback loop in which estrogen signaling further amplifies cytokine production, creating a self-sustaining inflammatory environment that promotes tumor progression. Understanding this cytokine–ER crosstalk provides novel insights into endometrial cancer pathogenesis and reveals potential therapeutic targets. Strategies that combine endocrine therapy with anti-inflammatory agents or cytokine pathway inhibitors may help overcome resistance and improve clinical outcomes in selected patients. Further mechanistic studies and clinical trials are needed to validate the prognostic and therapeutic relevance of IL-6 and IL-17 in hormone-responsive endometrial cancer

SCFFBXW11 Complex Targets Interleukin-17 Receptor A for Ubiquitin–Proteasome-Mediated Degradation

Interleukin-17 (IL-17) is a pro-inflammatory cytokine that participates in innate and adaptive immune responses and plays an important role in host defense, autoimmune diseases, tissue regeneration, metabolic regulation, and tumor progression. Post-translational modifications (PTMs) are crucial for protein function, stability, cellular localization, cellular transduction, and cell death. However, PTMs of IL-17 receptor A (IL-17RA) have not been investigated. Here, we show that human IL-17RA was targeted by F-box and WD repeat domain-containing 11 (FBXW11) for ubiquitination, followed by proteasome-mediated degradation. We used bioinformatics tools and biochemical techniques to determine that FBXW11 ubiquitinated IL-17RA through a lysine 27-linked polyubiquitin chain, targeting IL-17RA for proteasomal degradation. Domain 665-804 of IL-17RA was critical for interaction with FBXW11 and subsequent ubiquitination. Our study demonstrates that FBXW11 regulates IL-17 signaling pathways at the IL-17RA level

NMR Fragment-Based Screening against Tandem RNA Recognition Motifs of TDP-43

The TDP-43 is originally a nuclear protein but translocates to the cytoplasm in the pathological condition. TDP-43, as an RNA-binding protein, consists of two RNA Recognition Motifs (RRM1 and RRM2). RRMs are known to involve both protein-nucleotide and protein-protein interactions and mediate the formation of stress granules. Thus, they assist the entire TDP-43 protein with participating in neurodegenerative and cancer diseases. Consequently, they are potential therapeutic targets. Protein-observed and ligand-observed nuclear magnetic resonance (NMR) spectroscopy were used to uncover the small molecule inhibitors against the tandem RRM of TDP-43. We identified three hits weakly binding the tandem RRMs using the ligand-observed NMR fragment-based screening. The binding topology of these hits is then depicted by chemical shift perturbations (CSP) of the 15N-labeled tandem RRM and RRM2, respectively, and modeled by the CSP-guided High Ambiguity Driven biomolecular DOCKing (HADDOCK). These hits mainly bind to the RRM2 domain, which suggests the druggability of the RRM2 domain of TDP-43. These hits also facilitate further studies regarding the hit-to-lead evolution against the TDP-43 RRM domain.</jats:p