Atypical phosphatase DUSP11 inhibition promotes nc886 expression and potentiates gemcitabine-mediated cell death through NF-kB modulation.

Autor: Santos VS; Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil., Vieira GM; Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil., Ruckert MT; Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil., Andrade PV; Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil., Nagano LF; Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil., Brunaldi MO; Department of Pathology and Forensic Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil., Dos Santos JS; Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil., Silveira VS; Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil. vsilveira@fmrp.usp.br.; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. vsilveira@fmrp.usp.br.; Department of Medicine, Harvard Medical School, Boston, MA, USA. vsilveira@fmrp.usp.br.
Jazyk: angličtina
Zdroj: Cancer gene therapy [Cancer Gene Ther] 2024 Sep; Vol. 31 (9), pp. 1402-1411. Date of Electronic Publication: 2024 Jul 24.
DOI: 10.1038/s41417-024-00804-5
Abstrakt: Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest cancers among all solid tumors. First-line treatment relies on gemcitabine (Gem) and despite treatment improvements, refractoriness remains a universal challenge. Attempts to decipher how feedback-loops control signaling pathways towards drug resistance have gained attention in recent years, particularly focused on the role of phosphatases. In this study, a CRISPR/Cas9-based phenotypic screen was performed to identify members from the dual-specificity phosphatases (DUSP) family potentially acting on Gem response in PDAC cells. The approach revealed the atypical RNA phosphatase DUSP11 as a potential target, whose inhibition creates vulnerability of PDAC cells to Gem. DUSP11 genetic inhibition impaired cell survival and promoted apoptosis, synergistically enhancing Gem cytotoxicity. In silico transcriptome analysis of RNA-seq data from PDAC human samples identified NF-ĸB signaling pathway highly correlated with DUSP11 upregulation. Consistently, Gem-induced NF-ĸB phosphorylation was blocked upon DUSP11 inhibition in vitro. Mechanistically, we found that DUSP11 directly impacts nc886 expression and modulates PKR-NF-ĸB signaling cascade after Gem exposure in PDAC cells resulting in resistance to Gem-induced cell death. In conclusion, this study provides new insights on DUSP11 role in RNA biology and Gem response in PDAC cells.
(© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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