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Titel:

AGR2-Dependent Nuclear Import of RNA Polymerase II Constitutes a Specific Target of Pancreatic Ductal Adenocarcinoma in the Context of Wild-Type p53.

Dokumenttyp:
Journal Article; Research Support, Non-U.S. Gov't
Autor(en):
Zhang, Zhiheng; Li, Hongzhen; Deng, Yibin; Schuck, Kathleen; Raulefs, Susanne; Maeritz, Nadja; Yu, Yuanyuan; Hechler, Torsten; Pahl, Andreas; Fernández-Sáiz, Vanesa; Wan, Yuan; Wang, Guosheng; Engleitner, Thomas; Öllinger, Rupert; Rad, Roland; Reichert, Maximilian; Diakopoulos, Kalliope N; Weber, Verena; Li, Jingjing; Shen, Shanshan; Zou, Xiaoping; Kleeff, Jörg; Mihaljevic, Andre; Michalski, Christoph W; Algül, Hana; Friess, Helmut; Kong, Bo
Abstract:
BACKGROUND & AIMS: Promoted by pancreatitis, oncogenic KrasG12D 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. METHODS: A mouse model of inflammation-accelerated KrasG12D-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. RESULTS: We found that Agr2 is up-regulated in ADM-to-pancreatic intraepithelial neoplasia transition in inflammation and KrasG12D-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. CONCLUSIONS: 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.
Zeitschriftentitel:
Gastroenterology
Jahr:
2021
Band / Volume:
161
Heft / Issue:
5
Seitenangaben Beitrag:
1601-1614.e23
Volltext / DOI:
doi:10.1053/j.gastro.2021.07.030
PubMed:
http://view.ncbi.nlm.nih.gov/pubmed/34303658
Print-ISSN:
0016-5085
TUM Einrichtung:
II. Medizinische Klinik und Poliklinik (Gastroenterologie); III. Medizinische Klinik und Poliklinik (Hämatologie / Onkologie); Klinik und Poliklinik für Chirurgie; Lehrstuhl für Tumormetabolismus (Prof. Algül); Professur für Translationale gastroenterologische Onkologie (Prof. Rad)
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