Paraoxonase 2 (PON2) plays a limited role in murine lung tumorigenesis

Abstract

Paraoxonase 2 (PON2) is a multifunctional intracellular enzyme that has received growing attention for its ability to modulate various aspects of normal and malignant cellular physiology. Recent research has revealed that PON2 is upregulated in tissues from patients with various types of solid tumors and hematologic cancers, likely due to its ability to suppress oxidative stress and evade apoptosis. However, the effects of PON2 on pulmonary oncogenesis are unknown. Here, we conducted studies to investigate how PON2 influences lung cancer cell proliferation in vitro and lung tumorigenesis in vivo using a variety of cellular and animal models. It was found that PON2 expression deficiency hampered the proliferation of cultured lung cancer cells with concomitant cell cycle arrest at the G1 phase. In addition, the loss of endogenous PON2 expression impaired key aspects of oxidative metabolism in lung adenocarcinoma cells. Moreover, we investigated how the interplay between PON2 expression in lung tumors and host mice influences lung tumor initiation and progression. PON2 status in both transplanted tumor cells and mice failed to influence the development of subcutaneously grafted Lewis lung carcinoma (LLC) tumors, orthotopically implanted LLC tumors, and oncogenic Kras-driven primary lung adenocarcinoma tumors. Importantly, the frequencies of tumor-infiltrating myeloid subsets that include myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages were not impacted by PON2 expression in LLC tumor-bearing mice. Overall, our studies indicate that PON2 plays a limited role in murine lung tumorigenesis.

Contribution of the Paraoxonase-2 Enzyme to Cancer Cell Metabolism and Phenotypes

“…Induced enzyme knockdown and knockout significantly impaired cell proliferation and promoted cell cycle arrest in murine Lewis lung carcinoma (LCC) cell line and human A549 and NCI-HI1299 lung adenocarcinoma cells. Subsequent investigation of the impact of PON2 on cellular bioenergetics and metabolism revealed that enzyme loss markedly reduced glycolysis, tricarboxylic acid cycle activity, and de novo pyrimidine nucleotide biosynthesis [39]. As previously reported, also in lung cancer, PON2 overexpression was found to counteract programmed cell death by balancing ROS production.…”

“…It was demonstrated that PON2 upregulation can positively influence different processes associated with intracellular metabolism, such as glucose intake and consumption through glycolysis (and not by the pentose phosphate pathway), as well as the tricarboxylic acid cycle (TCA) and pyrimidine nucleotide biosynthesis. A high intracellular glucose level together with downstream intermediates of the glycolytic and TCA pathways contribute to the inhibition of AMP-activated protein kinase (AMPK), which in turn promotes tumor growth and metastasis [38,39].…”

New Treatment Horizons in Uveal and Cutaneous Melanoma

“…Paraoxonase-2 ( PON2 ) is another notable biomarker, with significant upregulation observed in melanomas compared to control nevi. PON2 expression correlates with important prognostic parameters, indicating its potential as a prognostic biomarker and its involvement in melanoma cell resistance to chemotherapy [ 122 , 123 , 124 ]. Moreover, the transcription factor Nrf2 has been linked to an altered redox homeostasis in melanomas, influencing phenotype switching.…”

Antiapoptotic PON2 expression and its clinical implications in locally advanced oral squamous cell carcinoma

“… 4 Studies have shown that PON2 expression is upregulated in tumor tissues compared with their corresponding normal tissues across various cancer types, including ovarian, breast, prostate, lung, colon, bladder, and leukemia. 5 , 6 , 7 …”

“…PON2 , a multifunctional enzyme, has gained attention because of its involvement in cellular homeostasis, lipid metabolism, and antiapoptotic properties 4 . Studies have shown that PON2 expression is upregulated in tumor tissues compared with their corresponding normal tissues across various cancer types, including ovarian, breast, prostate, lung, colon, bladder, and leukemia 5–7 …”