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

ABSTRACT: 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-?B(NF-?B) 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-?B-cyclin B1 pathway and found that GPx3 strongly suppressed activation of the Erk-NF-?B-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.

SUBMITTER: An BC

PROVIDER: S-EPMC6160013 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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

An Byung Chull BC Choi Yoo-Duk YD Oh In-Jae IJ Kim Ju Han JH Park Jae-Il JI Lee Seung-Won SW

PloS one 20180927 9

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 inves ...[more]

PMID: 30260967

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Project description:MicroRNA (miR)-138 was found to have suppressive effects on the growth and metastasis of different human cancers. In this study, we aimed to investigate the regulatory mechanism of miR-138 in non-small cell lung cancer (NSCLC). We applied the Quantitative real-time PCR (qRT-PCR) to detect the miR-138 levels in NSCLC tissues (n=21) and cell lines, Bioinformatical predication, luciferase reporter assay and western blot to identify the target gene of miR-138. We also applied Cell transfection, MTT, transwell, and wound healing assays to reveal the role of miR-138 in NSCLC cell proliferation and malignant transformation. We observed that miR-138 expression level was significantly decreased in NSCLC tissues compared to their matched adjacent normal tissues. It was also downregulated in tissues with poor differentiation, advanced stage or lymph nodes metastasis, as well as in several NSCLC cell lines compared to normal lung epithelial cell. We further identified YAP1 as a direct target gene of miR-138, and observed that the protein level of YAP1 was negatively mediated by miR-138 in NSCLC A549 cells. Moreover, overexpression of miR-138 significantly inhibited A549 cell growth, invasion and migration, while knockdown of miR-138 enhanced such capacities. Further investigation showed that the cell proliferation capacity was higher in the miR-138+YAP1 group, when compared with that in the miR-138 group, suggesting that overexpression of YAP1 rescued the suppressive effects of miR-138 upregulation on NSCLC cell proliferation. However, we found no difference of cell invasion and migration capacities between miR-138+YAP1 group and miR-138 group. Finally, YAP1 was markedly upregulated in NSCLC tissues compared to their marched adjacent normal tissues. Its mRNA levels were reversely correlated with the miR-138 levels in NSCLC tissues. In summary, our study suggests that miR-138 may play a suppressive role in the growth and metastasis of NSCLC cells partly at least by targeting YAP1.

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

Publications

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

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