子宫内膜癌（ECa）是女性第四大常见癌症。癌基因 PELP1 在包括 ECa 在内的多种癌症中经常过度表达。我们最近生成了 SMIP34，这是一种 PELP1 的小分子抑制剂，可抑制 PELP1 致癌信号传导。在这项研究中，我们评估了 SMIP34 治疗 ECa 的有效性。用 SMIP34 处理已建立的和原代患者来源的 ECa 细胞，导致细胞活力、集落形成能力和细胞凋亡诱导显着降低。 SMIP34 增强了 mTOR 抑制剂降低 ECa 细胞活力的功效。 RNA-seq 分析表明 SMIP34 调节的基因与核糖体生物合成和真核翻译途径呈负相关。机制研究表明，对于核糖体生物发生至关重要的 Rix 复合物在 SMIP34 与 PELP1 结合后被破坏。生化测定证实 SMIP34 减少核糖体生物合成和新蛋白质合成。 SMIP34 还可有效降低体外 ECa 类器官和离体外植体中的细胞活力。重要的是，SMIP34 处理导致 ECa 异种移植物的生长显着减少。总的来说，这些发现强调了 SMIP34 在治疗 ECa 方面的潜力。本文受版权保护。版权所有。

Endometrial carcinoma (ECa) is the fourth most common cancer among women. The oncogene PELP1 is frequently overexpressed in a variety of cancers, including ECa. We recently generated SMIP34, a small-molecule inhibitor of PELP1 that suppresses PELP1 oncogenic signaling. In this study, we assessed the effectiveness of SMIP34 in treating ECa. Treatment of established and primary patient-derived ECa cells with SMIP34 resulted in a significant reduction of cell viability, colony formation ability and induction of apoptosis. SMIP34 enhanced the efficacy of mTOR inhibitors in reducing viability of ECa cells. RNA-seq analyses showed that SMIP34 regulated genes that are negatively correlated with ribosome biogenesis and eukaryotic translation pathways. Mechanistic studies showed that the Rix complex, which is essential for ribosomal biogenesis, is disrupted upon SMIP34 binding to PELP1. Biochemical assays confirmed that SMIP34 reduced ribosomal biogenesis and new protein synthesis. SMIP34 is also effective in reducing cell viability in ECa organoids in vitro and explants ex vivo. Importantly, SMIP34 treatment resulted in a significant reduction of the growth of ECa xenografts. Collectively, these findings underscore the potential of SMIP34 in treating ECa.This article is protected by copyright. All rights reserved.