Endocrine receptors play an essential role in tumor metabolic reprogramming and represent a promising therapeutic avenue in pancreatic ductal adenocarcinoma (PDAC). PDAC is characterized by a nutrient-deprived microenvironment. To meet their ascendant energy demands, cancer cells can internalize extracellular proteins via macropinocytosis. However, the roles of endocrine receptors in macropinocytosis are not clear. In this study, we found that progesterone receptor (PGR), a steroid-responsive nuclear receptor, is highly expressed in PDAC tissues obtained from both patients and transgenic LSL-Kras^G12D/+; LSL-Trp53^R172H/+; PDX1-cre (KPC) mice. Moreover, PGR knockdown restrained PDAC cell survival and tumor growth both in vitro and in vivo. Genetic and pharmacological PGR inhibition resulted in a marked attenuation of macropinocytosis in PDAC cells and subcutaneous tumor models, indicating the involvement of this receptor in macropinocytosis regulation. Mechanistically, PGR upregulated CDC42, a critical regulator in macropinocytosis, through PGR-mediated transcriptional activation. These data deepen the understanding of how the endocrine system influences tumor progression via a non-classical pathway and provide a novel therapeutic option for patients with PDAC.

内分泌受体在肿瘤代谢重编程中发挥着重要作用，是胰腺导管腺癌 (PDAC) 的一种有前景的治疗途径。PDAC 的特点是微环境缺乏营养。为了满足不断增长的能量需求，癌细胞可以通过巨胞饮作用内化细胞外蛋白质。然而，内分泌受体在巨胞饮作用中的作用尚不清楚。在这项研究中，我们发现黄体酮受体（PGR）是一种类固醇反应性核受体，在从患者和转基因LSL-Kras ^G12D/+获得的PDAC组织中高表达；LSL-Trp53 ^R172H/+ ; PDX1-cre (KPC) 小鼠。此外，PGR 敲低在体外和体内均抑制了 PDAC 细胞的存活和肿瘤生长。遗传和药理学 PGR 抑制导致 PDAC 细胞和皮下肿瘤模型中巨胞饮作用显着减弱，表明该受体参与巨胞饮调节。从机制上讲，PGR 通过 PGR 介导的转录激活上调 CDC42（巨胞饮作用的关键调节因子）。这些数据加深了对内分泌系统如何通过非经典途径影响肿瘤进展的理解，并为 PDAC 患者提供了一种新的治疗选择。