Targeting BPTF Sensitizes Pancreatic Ductal Adenocarcinoma to Chemotherapy by Repressing ABC-Transporters and Impairing Multidrug Resistance (MDR)

Cancers

Diego Navarro¹  Bruno Sainz¹  Marian Lozano Yagüe²  Raquel Blanco Martinez-Illescas²  Víctor Javier Sánchez-Arévalo Lobo²  Ángela Pastor Senovilla²  Raúl Muñoz Velasco²  Ana García García²  Paula Jiménez Sánchez²  Rosa María García-Martin³  José Luis Rodríguez Peralto³  Alfonsina Trento³ 

[1] Department of Cancer Biology, Instituto de Investigaciones Biomédicas Alberto Sols (IIBM), CSIC-UAM, 28029 Madrid, Spain;Molecular Oncology Group, Biosanitary Research Institute, Faculty of Experimental Sciences, Francisco de Vitoria University (UFV), 28223 Madrid, Spain;Pathology Department, Hospital 12 de Octubre, Av. Córdoba, s/n, 28041 Madrid, Spain;

关键词: BPTF;    pancreatic cancer;    ABC-transporters;    multidrug resistance;    gemcitabine;   

DOI  :  10.3390/cancers14061518

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown