Irbesartan overcomes gemcitabine resistance in pancreatic cancer by suppressing stemness and iron metabolism via inhibition of the Hippo/YAP1/c-Jun axis

作者：Tianxing Zhou, Yongjie Xie, Xupeng Hou, Weiwei Bai, Xueyang Li, Ziyun Liu, Quan Man, Jingyan Sun, Danqi Fu, Jingrui Yan, Zhaoyu Zhang, Yifei Wang, Hongwei Wang, Wenna Jiang, Song Gao, Tiansuo Zhao, Antao Chang, Xiuchao Wang, Hongxia Sun, Xiufeng Zhang, Shengyu Yang, Chongbiao Huang, Jihui Hao, Jing Liu · 发表于：Journal of Experimental & Clinical Cancer Research · 年份：2023 · DOI：10.1186/s13046-023-02671-8 · 被引用次数：79 · 研究领域：Hippo pathway signaling and YAP/TAZ、FOXO transcription factor regulation、Cancer Cells and Metastasis

Abstract Background Chemoresistance is the main reason for the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Thus, there is an urgent need to screen out new targets and compounds to reverse chemotherapeutic resistance. Methods We established a bio-bank of human PDAC organoid models, covering a representative range of PDAC tumor subtypes. We screened a library of 1304 FDA-approved compounds to identify candidates efficiently overcoming chemotherapy resistance. The effects of the compounds were evaluated with a CellTiter-Glo-3D assay, organoid apoptosis assay and in vivo patient-derived xenograft (PDX), patient-derived organoid (PDO) and LSL-Kras G12D/+ ; LSL-Trp53 R172H/+ ; Pdx1-Cre (KPC) genetically engineered mouse models. RNA-sequencing, genome editing, sphere formation assays, iron assays and luciferase assays were conducted to elucidate the mechanism. Results High-throughput drug screening of chemotherapy-resistant PDOs identified irbesartan, an angiotensin ‖ type 1 (AT1) receptor antagonist, which could synergistically enhance the ability of chemotherapy to kill PDAC cells. In vitro and in vivo validation using PDO, PDX and KPC mouse models showed that irbesartan efficiently sensitized PDAC tumors to chemotherapy. Mechanistically, we found that irbesartan decreased c-Jun expression by inhibiting the Hippo/YAP1 pathway and further overcame chemotherapy resistance in PDAC. We also explored c-Jun, a potential target of irbesartan, which can transcriptionally up...