IL1RAP Pulls a Double Shift in the Cysteine Factory

Abstract

Summary: Anoikis is a critical barrier to cancer cell metastasis. In this issue of Cancer Discovery, Zhang and colleagues identify that IL1 receptor accessory protein suppresses anoikis in Ewing sarcoma by promoting both the activity of the system Xc− cystine/glutamate antiporter and cystathionine γ-lyase (CTH) transcription to sustain cysteine levels for reactive oxygen species detoxification. See related article by Zhang et al., p. 2884.

A novel anoikis-related gene signature predicts prognosis in patients with head and neck squamous cell carcinoma and reveals immune infiltration

“…Normally, when normal epithelial cells detach, they lose critical survival factors and undergo a programmed cell death called anoikis (Nirmala and Lopus, 2020), while HNSCC metastatic tumor cells gain anoikis resistance, which allows them to begin curating away from the primary lesion (Braunholz et al, 2016;Liao et al, 2017;Shen et al, 2017). Owing of the fact that anchorage-dependent growth and epithelial-mesenchymal transition, two features associated with anoikis resistance, are critical steps in tumor progression and metastatic spread of cancer cells, anoikis dysregulation is now of particular interest to the scientific community (Talukdar et al, 2018;Corbet et al, 2020;Ye et al, 2020;Yoon and DeNicola, 2021;Yu et al, 2022). Multiple pathways can lead to the acquisition of anoikis resistance in HNSCC (Dey et al, 2015), and these highlight the concept of targeting anoikis-related genes to overcome HNSCC progression and metastasis (Kumar et al, 2010).…”

IL-1 Family Members in Bone Sarcomas

“…When xCT functions are reduced due to cystine depletion, IL1RAP induces cystathionine gamma lyase (CTH) for de novo cysteine synthesis. Therefore, IL1RAP maintains the cysteine and glutathione pools, which are essential for redox homeostasis, protection from ferroptosis (iron-dependent cell death induced by cystein depletion), and anoikis resistance [45,46]. Interestingly, high CTH expression was found to be associated with shorter event-free survival in two separate cohorts of patients with Ewing sarcoma, supporting a role for CTH in Ewing sarcoma malignancy [46].…”

“…Recent results have highlighted that IL-1RAP activities are not limited to the roles played in the context of the IL-1 family in immune cells as IL-1R co-receptors. By transforming fibroblasts with multiple oncogenes, IL-1RAP has emerged as a protein that is directly induced by the fusion oncoproteins EWS::FLI1 (but also EWS::ERG) that drive EWS [45,46]. EWS::FLI1 induced IL1RAP expression by recruiting the BAF/p300 complex to the IL1RAP enhancer [45,46].…”

“…By transforming fibroblasts with multiple oncogenes, IL-1RAP has emerged as a protein that is directly induced by the fusion oncoproteins EWS::FLI1 (but also EWS::ERG) that drive EWS [45,46]. EWS::FLI1 induced IL1RAP expression by recruiting the BAF/p300 complex to the IL1RAP enhancer [45,46]. An analysis of published RNA-sequencing datasets and the detection of IL-1RAP protein expression in human tumor samples, xenografts, and cultured EWS cell lines demonstrated that IL-1RAP was expressed at high levels in EWS and that high IL-1RAP expression was significantly correlated with lower event-free survival in three different EWS cohorts [46].…”

“…Indeed, IL-1RAP was involved in the suppression of anoikis, a mechanism of programmed cell death that occurs when cells detach from the extracellular matrix and that cancer cells must overcome to enable the metastatic process. In EWS cells, IL-1RAP provides a cytoprotective mechanism by giving the cells the ability to maintain redox homeostasis and replenish the cysteine and glutathione (GSH) pools, even when extracellular uptake is restricted, during the metastatic cascade [45,46].…”