Inflammation, Infection, Cancer and All That…The Role of Paraoxonases

Abstract

The paraoxonase (PON) gene family consists of three members, PON1, PON2 and PON3. All PON proteins possess antioxidant properties and lipo-lactonase activities, and are implicated in the pathogenesis of several inflammatory diseases including atherosclerosis, Alzheimer's, Parkinson's, diabetes and cancer. Despite the role of PON proteins in critical cellular functions and associated pathologies, the physiological substrates and molecular mechanisms by which PON proteins function as anti-inflammatory proteins remain largely unknown. PON1 is found exclusively extracellular and associated solely with high-density lipoprotein (HDL) particles in the circulation, and, in part, confers the anti-oxidant and anti-inflammatory properties associated with HDL. Recent studies demonstrated that the intracellular PON proteins; PON2 and PON3 (i) are associated with mitochondria and mitochondria-associated membranes, (ii) modulate mitochondria-dependent superoxide production, and (iii) prevent apoptosis. Overexpression of PON2 and PON3 genes protected (i) mitochondria from antimycin or oligomycin mediated mitochondrial dysfunction and (ii) ER stress and ER stress mediated mitochondrial dysfunction. These studies illustrate that the anti-inflammatory effects of PON2 and PON3 may, in part, be mediated by their role in mitochondrial and associated organelle function. Since oxidative stress as a result of mitochondrial dysfunction is implicated in the development of inflammatory diseases including atherosclerosis and cancer, these recent studies on PON2 and PON3 proteins may provide a mechanism for the scores of epidemiological studies that show a link between PON genes and numerous inflammatory diseases. Understanding such mechanisms will provide novel routes of intervention in the treatment of diseases associated with pro-inflammatory oxidative stress.

Paraoxonase 2 Serves a Proapopotic Function in Mouse and Human Cells in Response to the Pseudomonas aeruginosa Quorum-sensing Molecule N-(3-Oxododecanoyl)-homoserine Lactone

“…DKO R MEF expressed a large number of genes that were cancer-or growth-related, including both PON2 and PON3 (32,37,38). PON2 is overexpressed in a number of cancers, including leukemia, hepatocellular, and prostate (33)(34)(35)(36).…”

“…Among these cancer-related genes, PON2 exhibited the most significantly different expression in DKO R MEF (high expression) compared with DKO NR MEF (low expression) (Table 1). PON3, which is thought to have similar antioxidant, anti-inflammatory, and anti-apoptotic functions as PON2 (31,32), ranked 10 in this category of genes that exhibited the most significantly different expression in DKO R MEF versus DKO NR MEF. PON1 was not detected in MEF (0 mapped reads in all sequenced samples).…”

“…PON2 and PON3 appear also to serve antioxidant, anti-inflammatory, anti-ER stress, and anti-apoptotic functions (31,32). PON2 and PON3 are highly expressed in multiple cancers (33)(34)(35)(36)(37), and overexpression of PON3 protects against mitochondrial-triggered apoptosis (38 -40).…”

Genome-wide DNA methylation profiling of recurrent and non-recurrent chordomas

“…All 3 proteins prevent oxidative stress and have anti-inflammatory properties and are implicated in pathogenesis of several inflammatory diseases including cancer. 25 In summary, we have identified a preliminary set of differential and cancer-specific methylated loci in chordomas that may be useful for future research into this rare cancer type. …”

Biomarkers and schizophrenia: a qualitative review

“…Decreased levels of PON1 activity in FEP indicate lowered protection against lipid peroxidation and lowered anti-inflammatory potential [64]. Impaired antioxidant defence and increased levels of the lipid peroxidation product-malondialdehyde-were also detected in the serum of chronic SCZ patients [58,59].…”