Epigenetic and Glucocorticoid Receptor-Mediated Regulation of Glutathione Peroxidase 3 in Lung Cancer Cells

An, Byung Chull; Jung, Nak-Kyun; Park, Chun Young; Oh, In Jae; Choi, Yoo‐Duk; Park, Jae-Il; Lee, Seungwon

doi:10.14348/molcells.2016.0164

Cited by 29 publications

(22 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Plasma GPx (GPx3) is the most important selenoenzyme involved in deactivating ROS, acting via thioredoxin and glutathione as reduction co-substrates [ 21 , 26 ]. Recently, we demonstrated glucocorticoid receptor-mediated upregulation of GPx3 in lung cancer cells [ 27 ]. Downregulation of GPx3 via promoter hypermethylation occurs in many types of human cancer, suggesting that GPx3 acts as a tumor suppressor [ 28 , 29 ].…”

Section: Introductionmentioning

confidence: 99%

GPx3-mediated redox signaling arrests the cell cycle and acts as a tumor suppressor in lung cancer cell lines

Choi

et al. 2018

PLoS ONE

Self Cite

View full text Add to dashboard Cite

Glutathione peroxidase 3 (GPx3), a major scavenger of reactive oxygen species (ROS) in plasma, acts as a redox signal modulator. However, the mechanism underlying GPx3-mediated suppression of cancer cell growth is unclear. The aim of this study was to identify these mechanisms with respect to lung cancer. To enhance the redox modulating properties of GPx3, lung cancer cells were subjected to serum starvation for 12 h, resulting in ROS generation in the absence of oxidant treatment. We then investigated whether suppression of tumorigenesis under conditions of oxidative stress was dependent on GPx3. The results showed that GPx3 effectively suppressed proliferation, migration, and invasion of lung cancer cells under oxidative stress. In addition, GPx3 expression led to a significant reduction in ROS production by cancer cells and induced G2/M phase arrest. We also found that inactivation of cyclin B1 significantly suppressed by nuclear factor-κB(NF-κB) inactivation in lung cancer cells was dependent on GPx3 expression. To further elucidate the mechanism(s) underlying GPx3-medited suppression of tumor proliferation, we next examined the effect of GPx3-mediated redox signaling on the ROS-MKP3-extracellular signal-regulated kinase (Erk)-NF-κB-cyclin B1 pathway and found that GPx3 strongly suppressed activation of the Erk-NF-κB-cyclin B1 signaling cascade by protecting MKP3 (an Erk-specific phosphatase) from the effects of ROS. Thus, this study demonstrates for the first time that the GPx3 suppresses proliferation of lung cancer cells by modulating redox-mediated signals.

show abstract

Section: Introductionmentioning

confidence: 99%

GPx3-mediated redox signaling arrests the cell cycle and acts as a tumor suppressor in lung cancer cell lines

Choi

et al. 2018

PLoS ONE

Self Cite

View full text Add to dashboard Cite

show abstract

“…Expression of GPX3 is regulated by hypermethylation and glucocorticoid receptor-mediated mechanisms [8]. In addition, GPX3 is a direct estrogen receptor alpha target gene in white AT [9].…”

Section: Introductionmentioning

confidence: 99%

“…In addition, GPX3 is a direct estrogen receptor alpha target gene in white AT [9]. GPX3 acts as a modulator of redox signaling, has immunomodulatory function, catalyzes the detoxification of ROS, and has been identified as a tumor suppressor in different types of cancer [6, 8]. Oxidative stress contributes to AT dysfunction in obesity [10, 11], hence GPX3 may play a crucial role as local defense mechanism, particularly in obesity [5, 12].…”

Section: Introductionmentioning

confidence: 99%

Effects of Weight Loss on Glutathione Peroxidase 3 Serum Concentrations and Adipose Tissue Expression in Human Obesity

et al. 2018

View full text Add to dashboard Cite

Background/Aims: Altered expression and circulating levels of glutathione peroxidase 3 (GPX3) have been observed in obesity and type 2 diabetes (T2D) across species. Here, we investigate whether GPX3 serum concentrations and adipose tissue (AT) GPX3 mRNA expression are related to obesity and weight loss. Methods: GPX3 serum concentration was measured in 630 individuals, including a subgroup (n = 293) for which omental and subcutaneous (SC) GPX3 mRNA expression has been analyzed. GPX3 analyses include three interventions: 6 months after bariatric surgery (n = 80) or combined exercise/hypocaloric diet (n = 20) or two-step bariatric surgery (n = 24) studies. Results: Bariatric surgery-induced weight loss (–25.8 ± 8.4%), but not a moderate weight reduction of –8.8 ± 6.5% was associated with significantly reduced GPX3 serum concentrations. GPX3 mRNA is significantly higher expressed in AT from individuals with normal glucose metabolism compared to T2D patients. SC AT GPX3 expression is significantly higher in lean compared to obese as well as in insulin-sensitive compared insulin-resistant individuals with obesity. Weight loss after bariatric surgery causes a significant increase in SC AT GPX3 expression. AT GPX3 expression significantly correlates with age, BMI, fat distribution, insulin sensitivity (only SC AT), but not with circulating GPX3. Conclusion: Our data support the notion that SC AT GPX3 expression is associated with obesity, fat distribution and related to whole body insulin resistance.

show abstract

“…Multiple studies have reported that when compared with normal cells, cancer cells presented with changed metabolism, and increased ROS production . However, GPX3, an antioxidant enzyme, can induce the detoxification of ROS . GPX3 could detoxify ROS thus modulating redox‐mediated signals, by which GPX3 impedes lung cancer cell proliferation .…”

Section: Discussionmentioning

confidence: 82%

Glutathione peroxidase 3 (GPX3) suppresses the growth of melanoma cells through reactive oxygen species (ROS)‐dependent stabilization of hypoxia‐inducible factor 1‐α and 2‐α

Jiang

Zhao

et al. 2019

J of Cellular Biochemistry

View full text Add to dashboard Cite

In this study, we aimed to explore the mechanism of glutathione peroxidase 3 (GPX3) in the growth of malignant melanoma (MM) cells by hypoxia‐inducible factor‐1α (HIF1‐α) and HIF2‐α regulating the metabolism through reactive oxygen species (ROS). The messenger RNA and protein expression of GPX3, HIF1‐α, HIF2‐α in tissues, and cell lines were measured by reverse transcription‐quantitative PCR and Western blot analysis. A375 cells were transfected with GPX3 overexpression plasmid, small interfering RNA (siRNA) targeting GPX3, or siRNA targeting HIF1‐α/HIF2‐α to upregulate or downregulate the expression of GPX3 or HIF1‐α/HIF2‐α. The effects of H2O2 and N‐acetylcysteine (NAC) on the levels of HIF1‐α and HIF2‐α after overexpression of GPX3 were studied. The cell viability was detected by Cell Counting Kit‐8. The levels of ROS, glucose uptake and lactic acid production, oxidative phosphorylation, and glycolysis of cells were measured for assessment of cellular metabolism. The expression of GPX3 decreased, while ROS, HIF1‐α, and HIF2‐α increased in MM tissues and cells. Overexpression of GPX3 inhibited the viability of MM cells and the growth of melanoma xenografts. The overexpression of GPX3 reduced the glucose uptake, extracellular lactic acid content, and extracellular acidification rate and increased the oxygen consumption rate level. Overexpression of GPX3 could reduce the levels of HIF1‐α and HIF2‐α, which could regulate metabolic levels. GPX3 reduced ROS level in MM to inhibit HIF1‐α and HIF2‐α. The addition of H2O2 increased while NAC reduced the protein levels of HIF1‐α and HIF2‐α in the cells overexpressing GPX3. Our study demonstrates that GPX3 inhibits the growth of MM cells through its inhibitory effect on cell metabolic disorder by inhibiting HIF1‐α via regulating ROS.

show abstract

Epigenetic and Glucocorticoid Receptor-Mediated Regulation of Glutathione Peroxidase 3 in Lung Cancer Cells

Cited by 29 publications

References 41 publications

GPx3-mediated redox signaling arrests the cell cycle and acts as a tumor suppressor in lung cancer cell lines

GPx3-mediated redox signaling arrests the cell cycle and acts as a tumor suppressor in lung cancer cell lines

Effects of Weight Loss on Glutathione Peroxidase 3 Serum Concentrations and Adipose Tissue Expression in Human Obesity

Glutathione peroxidase 3 (GPX3) suppresses the growth of melanoma cells through reactive oxygen species (ROS)‐dependent stabilization of hypoxia‐inducible factor 1‐α and 2‐α

Contact Info

Product

Resources

About