Novos mecanismos de regulação do gene NAPRT em tecidos e tumores

As células cancerígenas precisam de níveis mais elevados de NAD (Nicotinamida adenina dinucleótido). Por isso, as enzimas envolvidas no metabolismo de NAD, como NAMPT e NAPRT, são alvos para o desenvolvimento de novas terapias anti tumorais. Neste trabalho, mostramos que NAMPT e NAPRT são regularmente expressos em tecidos normais mas não em células tumorais, e identificamos alguns mecanismos que regulam a expressão de NAPRT em tecidos e tumores, o que pode ter implicações terapêuticas.

Autores e Afiliações:
Sara Duarte-Pereira¹, Isabel Pereira-Castro^1,2, Sarah S Silva¹, Mariana G Correia¹, Célia Neto¹, Luís Teixeira da Costa^1,3, António Amorim^1,4,5, Raquel M Silva^1,6.
¹ IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.
² Gene Regulation Group, i3S/IBMC - Instituto de Investigação e Inovação em Saúde/Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
³ ICAAM - Instituto de Ciências Agrárias e Ambientais Mediterrânicas, University of Évora, Évora, Portugal.
⁴ Faculty of Sciences, University of Porto, Porto, Portugal.
⁵ Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
⁶ Institute of Biomedicine - iBiMED & IEETA, University of Aveiro, Aveiro, Portugal.

Abstract:
Nicotinamide adenine dinucleotide (NAD) is a cofactor in redox reactions and a substrate for NAD-consuming enzymes, such as PARPs and sirtuins. As cancer cells have increased NAD requirements, the main NAD salvage enzymes in humans, nicotinamide phosphoribosyltransferase (NAMPT) and nicotinate phosphoribosyltransferase (NAPRT), are involved in the development of novel anti-cancer therapies. Knowledge of the expression patterns of both genes in tissues and tumors is critical for the use of nicotinic acid (NA) as cytoprotective in therapies using NAMPT inhibitors. Herein, we provide a comprehensive study of NAPRT and NAMPT expression across human tissues and tumor cell lines. We show that both genes are widely expressed under normal conditions and describe the occurrence of novel NAPRT transcripts. Also, we explore some of the NAPRT gene expression mechanisms. Our findings underline that the efficiency of NA in treatments with NAMPT inhibitors is dependent on the knowledge of the expression profiles and regulation of both NAMPT and NAPRT.

Revista: Oncotarget

Link: http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=6538