PRDX6 promotes lung tumor progression via its GPx and iPLA2 activities

Yun, Hyung-Mun; Park, Kyung-Ran; Lee, Hee Peum; Lee, Dong Hun; Jo, Miran; Shin, Dea Hwan; Yoon, Do‐Young; Han, Sang Bae; Hong, Jin Tae

doi:10.1016/j.freeradbiomed.2014.02.001

Cited by 65 publications

(66 citation statements)

References 44 publications

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“…An increase in the number and size of urethane-induced adenocarcinomas and the growth of A549 and NCI-H460 human lung cancer cells in mice was attributed to activation of the JAK2/STAT3 pathway, but the deletion of either the GPx activity (C47S-Prdx6) or the aiPLA2 activity (S32A-Prdx6) of Prdx6 had no effect on phosphorylated (activated) JAK2/STAT3 expression in these cells (127,140). Although the authors concluded that either enzymatic activity by itself could support activation of the pathway, this conclusion is suspect since either Based on these various studies, a preliminary conclusion is that aiPLA 2 activity can support tumor growth, invasiveness, and metastasis.…”

Section: Cancer and Carcinogenesismentioning

confidence: 99%

“…Elevated expression levels for Prdx6 have been demonstrated in association with a broad variety of human cancers including lymphoma and cancer of the breast, esophagus, lung, liver, ovaries, pancreas, bladder, thyroid, gingiva, tongue, skin, and mesothelium among others (121)(122)(123)(124)(125)(126)(127)(128)(129)(130)(131)(132)(133).…”

Section: Cancer and Carcinogenesismentioning

confidence: 99%

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The phospholipase A2 activity of peroxiredoxin 6 [S]

Fisher

2018

Journal of Lipid Research

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Peroxiredoxin 6 (Prdx6) is a Ca 2+ -independent intracellular phospholipase A 2 (called aiPLA 2 )that is localized to cytosol, lysosomes, and lysosomal-related organelles. Activity is minimal at cytosolic pH but is increased significantly with enzyme phosphorylation, at acidic pH, and in the presence of oxidized phospholipid substrate; maximal activity with phosphorylated aiPLA 2 is ~2 µmol/min/mg protein. Prdx6 is a "moonlighting" protein that also expresses glutathione peroxidase and lysophosphatidylcholine acyl transferase activities.The catalytic site for aiPLA 2 activity is an S32-H26-D140 triad; S32-H26 is also the phospholipid binding site. Activity is inhibited by a serine "protease" inhibitor (diethyl p-nitrophenyl phosphate),an analogue of the PLA 2 transition state (1-hexadecyl-3-(trifluoroethyl)-sn-glycero-2-phosphomethanol, MJ33), and by two naturally occurring proteins (surfactant protein A and p67 phox ), but not by bromoenol lactone. aiPLA 2 activity has important physiological roles in the turnover (synthesis and degradation) of lung surfactant phospholipids, in the repair of peroxidized cell membranes, and in the activation of NADPH oxidase (NOX2). The enzyme has been implicated in acute lung injury, carcinogenesis, neurodegenerative diseases, diabetes, male infertility, and sundry other conditions although its specific roles have not been well defined. Protein mutations and animal models are now available to further investigate the roles of Prdx6-aiPLA 2 activity in normal and pathological physiology.

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Section: Cancer and Carcinogenesismentioning

confidence: 99%

Section: Cancer and Carcinogenesismentioning

confidence: 99%

The phospholipase A2 activity of peroxiredoxin 6 [S]

Fisher

2018

Journal of Lipid Research

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“…Inhibition of iPLA 2 ␤ , but not iPLA 2 ␥ , in p53-positive LNCaP cells was also found to be associated with activation of p38 and induction of reactive species, which leads to cell cycle arrest and cytostasis ( 375 ). Lung tumor growth in an in vivo allograft model is promoted by PRDX6, which is a bifunctional protein with glutathione peroxidase (GPx) and iPLA 2 ␤ activities ( 376 ). Nude mice bearing PRDX6-overexpressing lung cancer cells exhibited increases in tumor size and weight and increased expression of both GPx and iPLA 2 ␤ , and these outcomes were inhibited when a mutant PRDX6 was used, suggesting that PRDX6 promotes lung tumor growth via GPx and iPLA 2 ␤ .…”

Section: Ipla 2 ␤ and Diseasesmentioning

confidence: 99%

Calcium-independent phospholipases A2 and their roles in biological processes and diseases

Ramanadham

Ali

Ashley

et al. 2015

Journal of Lipid Research

161

190

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The Ca 2+ -independent phospholipases A 2 (iPLA 2 s) are part of a diverse family of PLA 2 s that hydrolyze the sn -2 substituent from membrane phospholipids to release a free fatty acid and a lysolipid ( 1, 2 ). These enzymes are ubiquitously expressed, and in contrast to secretory PLA 2 s (sPLA 2 s) and cytosolic PLA 2 s (cPLA 2 s), do not require Ca 2+ for either translocation or activity. Some of the fi rst descriptions of iPLA 2 activity were in the mid-to late-1980s with the identifi cation of a plasmalogen-selective PLA 2 in Abstract Among the family of phospholipases A 2 (PLA 2 s) are the Ca 2+ -independent PLA 2 s (iPLA 2 s) and they are designated group VI iPLA 2 s. In relation to secretory and cytosolic PLA 2 s, the iPLA 2 s are more recently described and details of their expression and roles in biological functions are rapidly emerging. The iPLA 2 s or patatin-like phospholipases (PNPLAs) are intracellular enzymes that do not require Ca 2+ for activity, and contain lipase (GXSXG) and nucleotide-binding (GXGXXG) consensus sequences. Though nine PNPLAs have been recognized, PNPLA8 (membraneassociated iPLA 2 ␥ ) and PNPLA9 (cytosol-associated iPLA 2 ␤ ) are the most widely studied and understood. The iPLA 2 s manifest a variety of activities in addition to phospholipase, are ubiquitously expressed, and participate in a multitude of biological processes, including fat catabolism, cell differentiation, maintenance of mitochondrial integrity, phospholipid remodeling, cell proliferation, signal transduction, and cell death. As might be expected, increased or decreased expression of iPLA 2 s can have profound effects on the metabolic state, CNS function, cardiovascular performance, and cell survival; therefore, dysregulation of iPLA 2 s can be a critical factor in the development of many diseases. This review is aimed at providing a general framework of the current understanding of the iPLA 2 s and discussion of the potential mechanisms of action of the iPLA 2 s and related involved lipid mediators. -Ramanadham, S

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“…It was shown that there was an almost threefold higher expression of PRDX6 and PRDX6 peroxidase activity in the normal lung tissue of the PRDX6-transgenic (Tg) mouse compared with the wild-type mouse [18]. Recently, we reported that PRDX6 promotes lung tumor in in vivo allograft and xenograft mouse models [19,20]. Thus, a growing number of studies are being Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/freeradbiomed performed to address unanswered questions about the functional roles of PRDX6 as a tumorigenic protein and its potential value as a therapeutic target to fight cancer.…”

Section: Introuctionmentioning

confidence: 99%