Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, China; Department of Surgery, Ulm University Hospital, Ulm University, Ulm, Germany.
Gastroenterology. 2021 Nov;161(5):1601-1614.e23. doi: 10.1053/j.gastro.2021.07.030. Epub 2021 Jul 23.
BACKGROUND & AIMS: Promoted by pancreatitis, oncogenic Kras triggers acinar cells' neoplastic transformation through acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia. Anterior gradient 2 (Agr2), a known inhibitor of p53, is detected at early stage of pancreatic ductal adenocarcinoma (PDAC) development. RNA polymerase II (RNAPII) is a key nuclear enzyme; regulation of its nuclear localization in mammalian cells represents a potential therapeutic target.
A mouse model of inflammation-accelerated Kras-driven ADM and pancreatic intraepithelial neoplasia development was used. Pancreas-specific Agr2 ablation was performed to access its role in pancreatic carcinogenesis. Hydrophobic hexapeptides loaded in liposomes were developed to disrupt Agr2-RNAPII complex.
We found that Agr2 is up-regulated in ADM-to-pancreatic intraepithelial neoplasia transition in inflammation and Kras-driven early pancreatic carcinogenesis. Genetic ablation of Agr2 specifically blocks this metaplastic-to-neoplastic process. Mechanistically, Agr2 directs the nuclear import of RNAPII via its C-terminal nuclear localization signal, undermining the ATR-dependent p53 activation in ADM lesions. Because Agr2 binds to the largest subunit of RNAPII in a peptide motif-dependent manner, we developed a hexapeptide to interfere with the nuclear import of RNAPII by competitively disrupting the Agr2-RNAPII complex. This novel hexapeptide leads to dysfunction of RNAPII with concomitant activation of DNA damage response in early neoplastic lesions; hence, it dramatically compromises PDAC initiation in vivo. Moreover, the hexapeptide sensitizes PDAC cells and patient-derived organoids harboring wild-type p53 to RNAPII inhibitors and first-line chemotherapeutic agents in vivo. Of note, this therapeutic effect is efficient across various cancer types.
Agr2 is identified as a novel adaptor protein for nuclear import of RNAPII in mammalian cells. Also, we provide genetic evidence defining Agr2-dependent nuclear import of RNAPII as a pharmaceutically accessible target for prevention and treatment in PDAC in the context of wild-type p53.
胰腺炎促进致癌性 Kras 通过腺泡到导管化生（ADM）和胰腺上皮内瘤变触发腺泡细胞的肿瘤转化。已知的 p53 抑制剂前梯度 2（Agr2）在胰腺导管腺癌（PDAC）发展的早期阶段被检测到。RNA 聚合酶 II（RNAPII）是一种关键的核酶；调节其在哺乳动物细胞中的核定位代表了一个潜在的治疗靶点。
使用炎症加速的 Kras 驱动的 ADM 和胰腺上皮内瘤变发展的小鼠模型。进行了胰腺特异性 Agr2 缺失以研究其在胰腺发生中的作用。开发了装载在脂质体中的疏水性六肽以破坏 Agr2-RNAPII 复合物。
我们发现 Agr2 在炎症和 Kras 驱动的早期胰腺癌变中的 ADM 到胰腺上皮内瘤变转化中上调。Agr2 的基因缺失特异性阻断了这种化生到肿瘤的过程。在机制上，Agr2 通过其 C 末端核定位信号指导 RNAPII 的核输入，破坏 ADM 病变中 ATR 依赖性 p53 激活。因为 Agr2 以肽基序依赖的方式与 RNAPII 的最大亚基结合，所以我们开发了一种六肽来通过竞争性破坏 Agr2-RNAPII 复合物来干扰 RNAPII 的核输入。这种新型六肽导致 RNAPII 功能障碍，并在早期肿瘤病变中激活 DNA 损伤反应；因此，它在体内显著损害了 PDAC 的起始。此外，该六肽在体内使携带野生型 p53 的 PDAC 细胞和患者来源的类器官对 RNAPII 抑制剂和一线化疗药物敏感。值得注意的是，这种治疗效果在各种癌症类型中都有效。
Agr2 被鉴定为哺乳动物细胞中 RNAPII 核输入的新型衔接蛋白。此外，我们提供了遗传证据，将 Agr2 依赖性 RNAPII 核输入定义为在野生型 p53 背景下预防和治疗 PDAC 的可药用靶点。
