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

Figure 1

Origin of pancreatic ductal adenocarcinoma. It is widely accepted that pancreatic ductal carcinoma (PDAC) arises from precursor lesions derived from ductal cells; however, recently another model has been proposed where PDAC arises from acinar cells through a process called “acinar to ductal metaplasia” (ADM). PanIN: Intraepithelial neoplasm; IPMN: Intraductal papillary mucinous neoplasm; MCN: Mucinous cystic neoplasm.

Figure 2

Domains and structural features of a classical nuclear receptor. A typical nuclear receptor (NR) consists of 6 region (A to F); region F may or may not be present. Region D (hinge) contains the nuclear localization signal (NLS); other NLSs may be present in region E. AF-1: Activator function 1; AF-2: Activator function 2.

Figure 3

Mechanisms of action of nuclear receptors. Type I nuclear receptors (NR) (steroid receptors) are complexed with heat shock proteins (HSP) and maintained in the cytoplasm in the absence of ligands. The other receptors are instead mainly nuclear and the ligands induce hetero- (for type II receptors) or homo-dimerization (for type III receptors). Furthermore, a group of receptors (type IV) whose regulation is poorly known act as monomers.

Figure 4

Peroxisome proliferator activated receptors and pancreatic ductal carcinoma. Peroxisome proliferator activated receptor (PPAR)γ acts as a tumor inhibitor at multiple levels, blocking cell cycle progression, inflammation, and cell invasion. NAG-1: Non steroidal anti-inflammatory drug-activated gene-1; Cox-2: Ciclooxigenase-2; NF-κB: Nuclear factor-κB.

Figure 5

Steroid receptors in pancreatic ductal carcinoma. A: Androgen receptor (AR) regulates cell proliferation and migration and it is activated by the inflammatory cytokine interleukin-6 (IL-6); B: The effect of estrogen receptors (ER) on cell proliferation depends on the concentrations of the ER modulators.

Figure 6

Clustal sequence alignment of human NR4As. Shaded sequences correspond to the DNA binding domain where homology among NR4A1-3 is very high.

Figure 7

Nur77 acts as a tumor suppressor and as tumor promoting gene in pancreatic ductal carcinoma, inducing pro-apototic and anti-proliferative genes or repressing pro-survival genes. Dashed lines: Effects yet to be demonstrated in pancreatic ductal adenocarcinoma (PDAC). TRAIL: Tumor necrosis factor-related apoptosis-inducing ligand; PARP: Poly(ADP-ribose) polymerase; RXR: Retinoid X receptor; ER: Endoplasmic reticulum.

Figure 8

Chicken ovalbumin upstream promoter transcription factor II is involved in the regulation of angiogenesis, invasion and tumor proliferation. Expression of chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) is induced by several pathways altered in pancreatic ductal carcinoma, including Wnt/β-catenin, RAS-MAPK and Hedgehog.