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Nuclear PLD1 combined with NPM1 induces gemcitabine resistance through tumorigenic IL7R in pancreatic adenocarcinoma

Authors :
Danqi Fu
Jingrui Yan
Zhaoyu Zhang
Yang Liu
Xiaoqing Ma
Jinsheng Ding
Shengyu Yang
Ran Zhao
Antao Chang
Chuntao Gao
Jing Liu
Tiansuo Zhao
Xiuchao Wang
Chongbiao Huang
Song Gao
Ying Ma
Bo Tang
Yukuan Feng
Hongwei Wang
Jihui Hao
Source :
Cancer Biology & Medicine, Vol 20, Iss 8, Pp 599-626 (2023)
Publication Year :
2023
Publisher :
China Anti-Cancer Association, 2023.

Abstract

Objective: Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant gastrointestinal cancer with a 5-year survival rate of only 9%. Of PDAC patients, 15%-20% are eligible for radical surgery. Gemcitabine is an important chemotherapeutic agent for patients with PDAC; however, the efficacy of gemcitabine is limited due to resistance. Therefore, reducing gemcitabine resistance is essential for improving survival of patients with PDAC. Identifying the key target that determines gemcitabine resistance in PDAC and reversing gemcitabine resistance using target inhibitors in combination with gemcitabine are crucial steps in the quest to improve survival prognosis in patients with PDAC. Methods: We constructed a human genome-wide CRISPRa/dCas 9 overexpression library in PDAC cell lines to screen key targets of drug resistance based on sgRNA abundance and enrichment. Then, co-IP, ChIP, ChIP-seq, transcriptome sequencing, and qPCR were used to determine the specific mechanism by which phospholipase D1 (PLD1) confers resistance to gemcitabine. Results: PLD1 combines with nucleophosmin 1 (NPM1) and triggers NPM1 nuclear translocation, where NPM1 acts as a transcription factor to upregulate interleukin 7 receptor (IL7R) expression. Upon interleukin 7 (IL-7) binding, IL7R activates the JAK1/STAT5 signaling pathway to increase the expression of the anti-apoptotic protein, BCL-2, and induce gemcitabine resistance. The PLD1 inhibitor, Vu0155069, targets PLD1 to induce apoptosis in gemcitabine-resistant PDAC cells. Conclusions: PLD1 is an enzyme that has a critical role in PDAC-associated gemcitabine resistance through a non-enzymatic interaction with NPM1, further promoting the downstream JAK1/STAT5/Bcl-2 pathway. Inhibiting any of the participants of this pathway can increase gemcitabine sensitivity.

Details

Language :
English
ISSN :
20953941
Volume :
20
Issue :
8
Database :
Directory of Open Access Journals
Journal :
Cancer Biology & Medicine
Publication Type :
Academic Journal
Accession number :
edsdoj.41f4acb910649a6b6434c404baaece3
Document Type :
article
Full Text :
https://doi.org/10.20892/j.issn.2095-3941.2023.0039