Cancer-associated Fibroblasts-mediated ATF4 Expression Promotes Malignancy and Gemcitabine Resistance in Pancreatic Cancer Via the TGF-β1/SMAD2/3 Pathway and ABCC1 Transactivation

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2021 Mar 30

PMID 33782384

Citations 42

Authors

Lusheng Wei

Qing Lin

Yanan Lu

Guolin Li

Leyi Huang

Zhiqiang Fu

Rufu Chen

Quanbo Zhou

Affiliations

Soon will be listed here.

Abstract

Cancer-associated fibroblasts (CAFs) contribute to malignant progression and chemoresistance in pancreatic ductal adenocarcinoma (PDAC). However, little is known about the underlying mechanism. In this study, we investigated the potential role and mechanisms of activating transcription factor 4 (ATF4) in CAFs-induced malignancy and gemcitabine resistance. We demonstrated that ATF4 is overexpressed in PDAC and associated with a poor prognosis. Silencing ATF4 expression decreased proliferation, colony formation, migration, gemcitabine sensitivity, and sphere formation. Subsequently, we revealed that CAFs secrete TGF-β1 to upregulate the expression of ATF4 in PDAC cells via the SMAD2/3 pathway and induce cancer progression, cancer stemness, and gemcitabine resistance. Furthermore, we demonstrated that ATF4 directly binds to the ABCC1 promoter region to activate transcription. In summary, these data demonstrate that CAFs contribute to malignancy and gemcitabine resistance in PDAC by upregulating the expression of ATF4 via the TGF-β1/SMAD2/3 axis and highlight that ATF4 is an attractive therapeutic target for combating gemcitabine resistance in PDAC.

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