Metabolites of Purine Nucleoside Phosphorylase (NP) in Serum Have the Potential to Delineate Pancreatic Adenocarcinoma

Abstract

Pancreatic Adenocarcinoma (PDAC), the fourth highest cause of cancer related deaths in the United States, has the most aggressive presentation resulting in a very short median survival time for the affected patients. Early detection of PDAC is confounded by lack of specific markers that has motivated the use of high throughput molecular approaches to delineate potential biomarkers. To pursue identification of a distinct marker, this study profiled the secretory proteome in 16 PDAC, 2 carcinoma in situ (CIS) and 7 benign patients using label-free mass spectrometry coupled to 1D-SDS-PAGE and Strong Cation-Exchange Chromatography (SCX). A total of 431 proteins were detected of which 56 were found to be significantly elevated in PDAC. Included in this differential set were Parkinson disease autosomal recessive, early onset 7 (PARK 7) and Alpha Synuclein (aSyn), both of which are known to be pathognomonic to Parkinson's disease as well as metabolic enzymes like Purine Nucleoside Phosphorylase (NP) which has been exploited as therapeutic target in cancers. Tissue Microarray analysis confirmed higher expression of aSyn and NP in ductal epithelia of pancreatic tumors compared to benign ducts. Furthermore, extent of both aSyn and NP staining positively correlated with tumor stage and perineural invasion while their intensity of staining correlated with the existence of metastatic lesions in the PDAC tissues. From the biomarker perspective, NP protein levels were higher in PDAC sera and furthermore serum levels of its downstream metabolites guanosine and adenosine were able to distinguish PDAC from benign in an unsupervised hierarchical classification model. Overall, this study for the first time describes elevated levels of aSyn in PDAC as well as highlights the potential of evaluating NP protein expression and levels of its downstream metabolites to develop a multiplex panel for non-invasive detection of PDAC.

An Integrated Meta-Analysis of Secretome and Proteome Identify Potential Biomarkers of Pancreatic Ductal Adenocarcinoma

“…ARHGDIA-a specific regulator of Rho protein exchange reactions crucial for JNK pathway-was previously identified by a bioinformatic pipeline that searched for candidate genes related to pancreatic cancer using protein-protein interactions and a shortest path approach [180]. Also, in accordance with our results, PARK7 was found to be significantly elevated in PDAC [181], correlated with tumor invasion and worse patients' outcome, and responsible for promoting invasion and metastasis of pancreatic cancer cells [182].…”

Pathway-directed weighted testing procedures for the integrative analysis of gene expression and metabolomic data

“…Along with adenosine, which was detected originally, these all react with the enzyme purine-nucleoside phosphorylase, an enzyme with oncogenic effects when dys-regulated [33]. Further, metabolites of purine nucleoside phosphorylase have been found to be potential serum biomarkers in pancreatic cancer [34]. Thus the use of gene expression weighting has drawn attention to new metabolite concepts that were missed when the two data types were analyzed separately.…”

PNP (Purine Nucleoside Phosphorylase)

“…Furthermore, Roberts et al showed that plasma PNP activity was higher also in patients with breast, gastric, colon, lung and ovarian cancers and lymphoma (Roberts et al, 2004). From the biomarker perspective, Vareed et al found that PNP levels were higher in sera from pancreatic adenocarcinoma patients and levels of PNPregulated metabolites in serum, guanosine and adenosine, were suitable to determine pancreatic adenocarcinoma and distinguish pancreatic adenocarcinoma from benign tumors (Vareed et al, 2011). Plasma PNP activity was also higher in patients with asthma than in either healthy subjects or patients with gout (Yamamoto et al, 1995).…”