Cholesterol desensitizes the response of endometrial cancer to progestin by attenuating progestin signaling

IF 14.6 1区医学 Q1 CELL BIOLOGY

Science Translational Medicine Pub Date : 2025-10-01 DOI:10.1126/scitranslmed.adp0064

Jiali Hu, Lulu Wang, Bingyi Yang, Shimin Zhao, Xiaoping Wan, Wei Liu, Qiaoying Lv, Wei Xu, Xiaojun Chen

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Abstract

Progestin is the primary fertility-preserving treatment for patients with endometrial cancer (EC) and its precursor lesions, endometrial atypical hyperplasia (EAH); however, a subset of patients exhibits a poor response. In this study, through the analysis of serum lipid differences, we found that progestin-resistant patients with EC/EAH exhibited reduced serum apolipoprotein A-I concentrations and increased cholesterol accumulation in endometrial tissue. Mechanistically, molecular docking simulations and cellular models confirmed that cellular cholesterol interfered with progestin-driven signaling by competing with progestin for binding to progesterone receptor B (PRB), thereby impairing its phosphorylation, nuclear translocation, and downstream gene activation. Substitution of leucine⁸⁸⁷ with alanine⁸⁸⁷ in PRB disrupted cholesterol binding but preserved progestin responsiveness. Furthermore, cholesterol-lowering therapy with rosuvastatin calcium restored progestin sensitivity in animal models and in a single-arm, open-label phase 2 clinical trial. Our work shows that cholesterol accumulation contributes to progestin resistance and that combining progestin with statins may enhance therapeutic efficacy in EC.

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胆固醇通过减弱黄体酮信号使子宫内膜癌对黄体酮的反应脱敏

黄体酮是子宫内膜癌（EC）及其前驱病变子宫内膜不典型增生（EAH）患者的主要保留生育能力的治疗方法；然而，一部分患者表现出较差的反应。本研究通过对血脂差异的分析，我们发现孕激素抵抗的EC/EAH患者血清载脂蛋白A-I浓度降低，子宫内膜组织胆固醇积累增加。在机制上，分子对接模拟和细胞模型证实，细胞胆固醇通过与黄体酮结合黄体酮受体B （PRB）竞争，从而干扰黄体酮驱动的信号传导，从而损害其磷酸化、核转运和下游基因激活。在PRB中用丙氨酸887取代亮氨酸887破坏了胆固醇结合，但保留了黄体酮的反应性。此外，在动物模型和单臂、开放标签的2期临床试验中，瑞舒伐他汀钙降胆固醇治疗恢复了黄体酮敏感性。我们的研究表明，胆固醇积累有助于黄体酮抵抗，黄体酮联合他汀类药物可以提高EC的治疗效果。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL

CiteScore

26.70

自引率

1.20%

发文量

309

审稿时长

1.7 months

期刊介绍： Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.