Expression and Intracellular Localization of Paraoxonase 2 in Different Types of Malignancies

Abstract

PON2 belongs to the paraoxonase protein family that consists of lactone hydrolyzing enzymes with different substrate specificities. Unlike other members of the family, PON2 exhibits substantial antioxidant activity, is localized predominantly inside the cell, and is ubiquitously expressed in all human tissues. Previously, it was proffered that defense against pathogens, such as Pseudomonas aeruginosa, is the main function of paraoxonases. However, recent findings have highlighted the important role played by PON2 in protection against oxidative stress, inhibition of apoptosis, and progression of various types of malignancies. In the current study, we performed a bioinformatic analysis of RNA and DNA sequencing data extracted from tumor samples taken from more than 10,000 patients with 31 different types of cancer and determined expression levels and mutations in the PON2 gene. Next, we investigated the intracellular localization of PON2 in multiple cancer cell lines and identified the proteins interacting with PON2 using the LC-MS/MS technique. Our data indicate that a high PON2 expression level correlates with a worse prognosis for patients with multiple types of solid tumors and suggest that PON2, when localized on the nuclear envelope and endoplasmic reticulum, may protect cancer cells against unfavorable environmental conditions and chemotherapy.

Insights into the role of paraoxonase 2 in human pathophysiology

“…Reportedly, PON2 could be involved in tumor survival and stress resistance. An elaborate clinical study, conducted on tumor samples taken from more than 10,000 patients with different types of cancer, showed a high expression of PON2 in multiple types of solid tumors, suggesting that overexpression of PON2 in cancer cells causes resistant to chemotherapy and other unfavorable conditions causing malignancy (Shakhparonov et al 2018 ). Similarly, overexpression of PON2 in bladder cancer cell lines led to a significant increase in cell proliferation and resistance to oxidative stress (Bacchetti et al 2017 ).…”

Paraoxonase 2 is critical for non-small cell lung carcinoma proliferation.

“…This might be attributed to different precancerous stages bearing various premalignant lesions in adjacent normal tissues [50]. These data highlight a correlation between PON2 expression and malignant transformation in human patients with NSCLC, consistent with a recent study revealing a negative correlation between PON2 expression and patient prognosis of many cancer types [42].…”

“…is upregulated in numerous and diverse tumor types [38], [42], these considerations necessitate further study of PON2's oncogenic contribution in other neoplastic tissues and cells.…”

“…As discussed in the introduction, a number of studies have correlated PON2 overexpression in a wide variety of solid tumors and blood cancers with tumorigenesis, disease progression, and chemotherapeutic sensitivity [34], [37], [38], [41], [42]. Of these studies, a limited number have focused on lung cancer in general [24], [42], but have failed to interrogate PON2 expression in NSCLC specifically. To determine the relative expression level of PON2 in NSCLC, we acquired lung tumor samples from 11 patients with NSCLC and compared PON2…”

Paraoxonases Activities and Polymorphisms in Elderly and Old-Age Diseases: An Overview

“…Moreover, PON-2 located in the nuclear envelope and endoplasmic reticulum, could protect cancer cells against unfavorable environmental conditions and against chemotherapy. Patients with glioblastoma, low grade glioma, liver hepatocellular carcinoma and acute myeloid leukemia, exhibiting higher expression of PON-2, had poor survival when compared with patients with lower PON-2 expression [195].…”