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© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Simple Summary

Pancreatic ductal adenocarcinoma is a devastating disease and an extremely chemoresistant tumour. In the present manuscript, we described the role of BPTF during tumour pancreatic ductal adenocarcinoma progression and in response to gemcitabine treatment, a gold standard treatment in this tumour type. Through different genetic approaches, we reduced BPTF levels in a panel of pancreatic ductal adenocarcinoma cell lines. We validated its therapeutic effect in cell cultures and in mouse models of pancreatic cancer. A reduction in BPTF levels impaired cell proliferation and sensitized pancreatic tumour cells to gemcitabine. We demonstrated that BPTF-silencing reduced the expression of several ABC-transporters, which are involved in gemcitabine resistance, and enhanced its accumulation in the tumour cell, improving its therapeutic effect.

Abstract

Pancreatic ductal adenocarcinoma (PDA) is characterized by an extremely poor prognosis due to its late diagnosis and strong chemoresistance to the current treatments. Therefore, finding new therapeutic targets is an urgent need nowadays. In this study, we report the role of the chromatin remodeler BPTF (Bromodomain PHD Finger Transcription Factor) as a therapeutic target in PDA. BPTF-silencing dramatically reduced cell proliferation and migration in vitro and in vivo in human and mouse PDA cell lines. Moreover, BPTF-silencing reduces the IC50 of gemcitabine in vitro and enhanced its therapeutic effect in vivo. Mechanistically, BPTF is required for c-MYC recruitment to the promoter of ABC-transporters and its downregulation facilitates gemcitabine accumulation in tumour cells, increases DNA damage, and a generates a strong synergistic effect in vivo. We show that BPTF is a therapeutic target in pancreatic ductal adenocarcinoma due to its strong effect on proliferation and in response to gemcitabine.

Details

Title
Targeting BPTF Sensitizes Pancreatic Ductal Adenocarcinoma to Chemotherapy by Repressing ABC-Transporters and Impairing Multidrug Resistance (MDR)
Author
Raúl Muñoz Velasco 1   VIAFID ORCID Logo  ; Paula Jiménez Sánchez 1 ; Ana García García 1   VIAFID ORCID Logo  ; Raquel Blanco Martinez-Illescas 1 ; Ángela Pastor Senovilla 1 ; Marian Lozano Yagüe 1 ; Trento, Alfonsina 2 ; García-Martin, Rosa María 2 ; Navarro, Diego 3 ; SainzJr, Bruno 4   VIAFID ORCID Logo  ; Rodríguez Peralto, José Luis 2 ; Sánchez-Arévalo Lobo, Víctor Javier 1   VIAFID ORCID Logo 

 Molecular Oncology Group, Biosanitary Research Institute, Faculty of Experimental Sciences, Francisco de Vitoria University (UFV), 28223 Madrid, Spain; [email protected] (R.M.V.); [email protected] (P.J.S.); [email protected] (A.G.G.); [email protected] (R.B.M.-I.); [email protected] (Á.P.S.); [email protected] (M.L.Y.); Pathology Department, Hospital 12 de Octubre, Av. Córdoba, s/n, 28041 Madrid, Spain; [email protected] (A.T.); [email protected] (R.M.G.-M.); [email protected] (J.L.R.P.) 
 Pathology Department, Hospital 12 de Octubre, Av. Córdoba, s/n, 28041 Madrid, Spain; [email protected] (A.T.); [email protected] (R.M.G.-M.); [email protected] (J.L.R.P.) 
 Department of Cancer Biology, Instituto de Investigaciones Biomédicas Alberto Sols (IIBM), CSIC-UAM, 28029 Madrid, Spain; [email protected] (D.N.); [email protected] (B.S.J.); Chronic Diseases and Cancer Area 3-Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28029 Madrid, Spain 
 Department of Cancer Biology, Instituto de Investigaciones Biomédicas Alberto Sols (IIBM), CSIC-UAM, 28029 Madrid, Spain; [email protected] (D.N.); [email protected] (B.S.J.); Chronic Diseases and Cancer Area 3-Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28029 Madrid, Spain; Centro de Investigación Biomédica en Red, Área Cáncer, CIBERONC, ISCIII, 28029 Madrid, Spain 
First page
1518
Publication year
2022
Publication date
2022
Publisher
MDPI AG
e-ISSN
20726694
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2642355705
Copyright
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.