424 LSR promotes tumor progression by regulating signal transduction of apoptosis and ferroptosis in endometrial cancer

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<h3>Introduction/Background*</h3> Since advanced endometrial cancer (EC) remains a disease with a poor prognosis, the development of novel therapeutic agents are warranted. Previously, we identified lipolysis-stimulated lipoprotein receptor (LSR) as a highly expressed molecule in ovarian cancer (OC) cells and developed an anti-LSR monoclonal antibody. The antibody significantly suppressed tumor growth in EC as well as OC, however the mechanism is largely unclear, and the function of LSR in cancer cells needs to be elucidated. In this study, we focused on apoptosis and ferroptosis in programmed cell deaths and investigated the function of LSR using in vitro and bioinformatic analysis. <h3>Methodology</h3> We evaluated LSR expression by immunohistochemistry and analyzed overall survival (OS) and clinicopathological features in 228 EC patients. To investigate the mechanism by which LSR affects the prognosis of EC patients, the pathway enrichment analysis was conducted using published proteomic data of EC. In vitro analyses were performed using two human EC cell lines (HEC1 and HEC116) and the activity of signaling pathways were examined by western blotting. <h3>Result(s)*</h3> Patients were divided into two groups based on LSR expression; High (strongly stained in ≥25% of the lesion, n=153) and Low (strongly stained in &lt;25% of the lesion, n=75) groups. 5-year OS rate in High group was significantly lower than Low group (hazard ratio: 3.53, 95% confidence interval: 1.35 – 9.24, p=0.01). The pathway analysis demonstrated that proteins correlated with high LSR expression were enriched in MAPK signaling pathway, glutathione metabolism, and cysteine and methionine metabolism. In vitro and western blot analyses showed that LSR-knockdown suppressed EC cell proliferation and the phosphorylation of MEK/ERK signaling pathway including MEK1/2, ERK1/2, and p90RSK. ERK1/2-knockdown also suppressed cell proliferation, suggesting that LSR contributed to EC cell proliferation through the MEK/ERK pathway, which is one of the apoptotic signaling pathway. In addition, LSR-knockdown suppressed the expression of cystine/glutamate antiporter (xCT) and GPX4, which inhibit ferroptosis by regulating cystine/glutamine metabolism, as determined by western blot analysis. <h3>Conclusion*</h3> LSR contributes to tumor progression and poor prognosis by regulating apoptotic and ferroptotic signaling pathways in endometrial cancer. LSR may be a novel therapeutic target molecule in EC.