胰腺导管腺癌（PDAC）是最具侵袭性的恶性肿瘤之一，其预后非常糟糕。作为DNA合成的竞争性抑制剂，吉西他滨是治疗各阶段PDAC的基石药物。然而，吉西他滨的治疗效果常常受到耐药性的阻碍，并且其潜在机制仍然很大程度上未知。尽管 PDAC 风险与内分泌失调之间存在关联，但尚不清楚他们对化疗药物的反应是否受到内分泌调节剂的调节。在这里，我们证明催乳素受体 (PRLR) 在 PDAC 的体外和体内治疗中与吉西他滨具有协同作用。有趣的是，PRLR 促进 miR-4763-3p 和 miR-3663-5p 的表达，这两种新的 miRNA 的功能尚不清楚。此外，对哺乳小鼠模型肿瘤转录组测序数据的分析丰富了 PPP 途径，这是一种多功能代谢途径。 PPP途径除了提供能量外，主要提供合成代谢的各种原料。我们证明戊糖磷酸途径 (PPP) 的两种关键酶 G6PD 和 TKT 是 miR-4763-3p 和 miR-3663-5p 直接靶向的。值得注意的是，miR-4763-3p 和 miR-3663-5p 减少了 PPP 途径的核苷酸合成，从而增加了吉西他滨的敏感性。因此，PRLR 利用这两种 miRNA 抑制 PPP 和核苷酸合成，随后提高 PDAC 细胞对吉西他滨的敏感性。此外，来自 LSL-KrasG12D/ 、LSL-Trp53R172H/ 和 PDX1-cre (KPC) 小鼠的 PDAC 组织和肿瘤表现出 PRLR 的下调。 PDAC 组织的亚硫酸氢盐测序揭示 PRLR 下调是由于表观遗传甲基化。在这项研究中，我们首次证明内分泌受体 PRLR 通过增强两种新的 miRNA 来改善吉西他滨的效果，这两种 miRNA 通过同时抑制两种必需酶来阻断 PPP 途径和核苷酸合成。 PRLR-miRNAs-PPP 轴可作为补充 PDAC 化疗优势的可能治疗靶点。© 2024 美国实验生物学会联合会。

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, with a notoriously dismal prognosis. As a competitive inhibitor of DNA synthesis, gemcitabine is the cornerstone drug for treating PDAC at all stages. The therapeutic effect of gemcitabine, however, is often hindered by drug resistance, and the underlying mechanisms remain largely unknown. It is unclear whether their response to chemotherapeutics is regulated by endocrine regulators, despite the association between PDAC risk and endocrine deregulation. Here, we show that prolactin receptor (PRLR) synergizes with gemcitabine in both in vitro and in vivo treatment of PDAC. Interestingly, PRLR promotes the expression of miR-4763-3p and miR-3663-5p, two novel miRNAs whose functions are unknown. Furthermore, the analysis of transcriptome sequencing data of tumors from lactating mouse models enriches the PPP pathway, a multifunctional metabolic pathway. In addition to providing energy, the PPP pathway mainly provides a variety of raw materials for anabolism. We demonstrate that two key enzymes of the pentose phosphate pathway (PPP), G6PD and TKT, are directly targeted by miR-4763-3p and miR-3663-5p. Notably, miR-4763-3p and miR-3663-5p diminish the nucleotide synthesis of the PPP pathway, thereby increasing gemcitabine sensitivity. As a result, PRLR harnesses these two miRNAs to suppress PPP and nucleotide synthesis, subsequently elevating the gemcitabine sensitivity of PDAC cells. Also, PDAC tissues and tumors from LSL-KrasG12D/+, LSL-Trp53R172H/+, and PDX1-cre (KPC) mice exhibit downregulation of PRLR. Bisulfite sequencing of PDAC tissues revealed that PRLR downregulation is due to epigenetic methylation. In this study, we show for the first time that the endocrine receptor PRLR improves the effects of gemcitabine by boosting two new miRNAs that block the PPP pathway and nucleotide synthesis by inhibiting two essential enzymes concurrently. The PRLR-miRNAs-PPP axis may serve as a possible therapeutic target to supplement chemotherapy advantages in PDAC.© 2024 Federation of American Societies for Experimental Biology.