Nuclear receptors and pathogenesis of pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a median overall survival time of 5 mo and the five years survival less than 5%, a rate essentially unchanged over the course of the years. A well defined progression model of accumulation of genetic alterations ranging from single point mutations to gross chromosomal abnormalities has been introduced to describe the origin of this disease. However, due to the its subtle nature and concurring events PDAC cure remains elusive. Nuclear receptors (NR) are members of a large superfamily of evolutionarily conserved ligand-regulated DNA-binding transcription factors functionally involved in important cellular functions ranging from regulation of metabolism, to growth and development. Given the nature of their ligands, NR are very tempting drug targets and their pharmacological modulation has been widely exploited for the treatment of metabolic and inflammatory diseases. There are now clear evidences that both classical ligand-activated and orphan NR are involved in the pathogenesis of PDAC from its very early stages; nonetheless many aspects of their role are not fully understood. The purpose of this review is to highlight the striking connections that link peroxisome proliferator activated receptors, retinoic acid receptors, retinoid X receptor, androgen receptor, estrogen receptors and the orphan NR Nur, chicken ovalbumin upstream promoter transcription factor II and the liver receptor homologue-1 receptor to PDAC development, connections that could lead to the identification of novel therapies for this disease.

Keywords: Peroxisome proliferator activated receptor, Pancreatic intraepithelial neoplasia, COUP-TFII, Nuclear receptors, Orphan nuclear receptor, Nuclear receptors 4A2, Nuclear receptors 2F2, Pancreatic cancer, Retinoid X receptor, Testicular receptor 3

Core tip: Pancreatic cancer is a devastating disease with well defined genetic alterations made deadly by its subtle nature and the lack of effective drugs. Nuclear receptors (NR) are ligand-regulated transcription factors involved in important cellular functions and tempting targets for drug development. There are now evidences that classical ligand-activated peroxisome proliferator activated receptors, retinoic acid receptors, retinoid X receptors, androgen receptor, estrogen receptors and orphan Nur, chicken ovalbumin upstream promoter transcription factor II and liver receptor homologue-1 NR are involved in the pathogenesis of pancreatic cancer. No clinical application of these NR in pancreatic cancer cure is reported but a more comprehensive analysis of NR action could lead to the identification of new treatments for this disease.