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-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.

Inhibition of pyruvate dehydrogenase kinase redirects NSCLC cell metabolism and counteracts development of resistance to epidermal growth factor receptor tyrosine kinase inhibitors

“…Interestingly, and in accordance t our ndings, reduced expression of GPX3 has been shown to be linked to increased proliferation rate in NSCLC by modulating redox mediated signals [105]. Further, GPX2 is associated with invasion, metastasis and tumor growth, as GPX2 knock down reduced levels of EMT markers such as vimentin, SNAI1 and MMP2 [106].…”

Potential relationship between the selenoproteome and cancer

“…Lower levels of GPX3, SELENOW, SELENOK, SELENBP1 and SECISBP2 in lung adenocarcinoma were associated with poor survival, while high levels of GPX3 in lung squamous cell carcinoma were associated with poor survival, possibly related to EMT activation. Recently, it was shown that GPX3 can inhibit the proliferation of lung cancer cells ( 49 ), and GPX3 levels, which can be regulated by methylation, were lower in lung cancer patients ( 50 , 51 ). In this study, hypermethylation of GPX3 can inhibit GPX3 expression in lung adenocarcinoma, while there was no difference in methylation between lung squamous cell carcinoma and normal tissue.…”

Extracellular Glutathione Peroxidase GPx3 and Its Role in Cancer

“…Nonetheless, antioxidant enzymes, including the GPx family members, are important regulators of these signaling cascades by manipulating levels of oxidants at cellular redox signaling hubs [28,85]. We highlight several studies in Section 3.2 where GPx3 has been implicated in modulating the activity of redox signaling pathways in cancer cells [32,[86][87][88][89][90].…”

“…Gene hypermethylation Poor patient outcome, potential biomarker [125] Inhibit activation of Erk-NF-κB-cyclin B1 pathway [86] Melanoma Gene hypermethylation Cancer progression, poor patient outcome [111] Inhibit expression of hypoxia-inducible factors 1α and 2α [89] [116] Myeloid leukemia N/D Cancer progression, poor patient outcome [116,129] Ovarian cancer N/D Cancer cell survival under anchorage independence and oxidative stress [14] Ovarian clear cell adenocarcinoma N/D Chemoresistance [130] As summarized in Table 1, several studies have reported a decrease or loss of GPx3 expression in tumor tissues [61][62][63]86,87,[109][110][111][112][113][114][115]. In many of these cancers, downregulation of GPx3 parallels cancer progression, and is often associated with poor patient outcome [62,90,109,110,123].…”