PAICS, a De Novo Purine Biosynthetic Enzyme, Is Overexpressed in Pancreatic Cancer and Is Involved in Its Progression.

Autor:	Agarwal S; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL., Chakravarthi BVSK; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL., Kim HG; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL., Gupta N; Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL., Hale K; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL., Balasubramanya SAH; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL., Oliver PG; Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL; Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL., Thomas DG; Department of Pathology, University of Michigan, Ann Arbor, MI., Eltoum IA; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL; Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL., Buchsbaum DJ; Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL; Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL., Manne U; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL; Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL., Varambally S; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL; Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL. Electronic address: svarambally@uabmc.edu.
Jazyk:	angličtina
Zdroj:	Translational oncology [Transl Oncol] 2020 Jul; Vol. 13 (7), pp. 100776. Date of Electronic Publication: 2020 May 15.
DOI:	10.1016/j.tranon.2020.100776
Abstrakt:	Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with an extremely poor prognosis. There is an urgent need to identify new therapeutic targets and also understand the mechanism of PDAC progression that leads to aggressiveness of the disease. To find therapeutic targets, we analyzed data related to PDAC transcriptome sequencing and found overexpression of the de novo purine metabolic enzyme phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS). Immunohistochemical analysis of PDAC tissues showed high expression of the PAICS protein. To assess the biological roles of PAICS, we used RNA interference and knock down of its expression in PDAC cell lines that caused a reduction in PDAC cell proliferation and invasion. Furthermore, results of chorioallantoic membrane assays and pancreatic cancer xenografts demonstrated that PAICS regulated pancreatic tumor growth. Our data also showed that, in PDAC cells, microRNA-128 regulates and targets PAICS. PAICS depletion in PDAC cells caused upregulation in E-cadherin, a marker of the epithelial-mesenchymal transition. In PDAC cells, a BET inhibitor, JQ1, reduced PAICS expression. Thus, our investigations show that PAICS is a therapeutic target for PDAC and, as an enzyme, is amenable to targeting by small molecules. (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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