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

Yi, Zihan; Jiang, Lu; Zhao, Lei; Zhou, Meiling; Ni, Yueli; Yang, Yuye; Yang, Huixin; Yang, Lijuan; Zhang, Qiao; Kuang, Yingmin; Mingjia, Deng; Zhu, Yuechun

doi:10.1002/jcb.29240

Cited by 42 publications

(32 citation statements)

References 45 publications

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“…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].…”

Section: Disease Association With Aberrant Gpx3mentioning

confidence: 99%

“…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].…”

Section: Altered Gpx3 Expression and Role In Tumor Tissuesmentioning

confidence: 99%

“…GPx3 can also suppress the expression of matrix metalloproteinase 9 (MMP-9) by deactivating the focal adhesion kinase (FAK)-AKT pathway, leading to decreased invasiveness of esophageal squamous cell carcinoma cells [90]. The antitumor effects of GPx3 were also shown to be elicited by inhibiting HIF-1α and HIF-2α in melanoma cells as a consequence of increased ROS scavenging by GPx3 [89]. In prostate cancer, GPx3 overexpression induces downregulation of the oncogene c-met, although the mechanisms of this were not explored [109].…”

Section: Altered Gpx3 Expression and Role In Tumor Tissuesmentioning

confidence: 99%

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Extracellular Glutathione Peroxidase GPx3 and Its Role in Cancer

Chang

Worley

Phaëton

et al. 2020

Cancers

152

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Mammalian cells possess a multifaceted antioxidant enzyme system, which includes superoxide dismutases, catalase, the peroxiredoxin/thioredoxin and the glutathione peroxidase systems. The dichotomous role of reactive oxygen species and antioxidant enzymes in tumorigenesis and cancer progression complicates the use of small molecule antioxidants, pro-oxidants, and targeting of antioxidant enzymes as therapeutic approaches for cancer treatment. It also highlights the need for additional studies to investigate the role and regulation of these antioxidant enzymes in cancer. The focus of this review is on glutathione peroxidase 3 (GPx3), a selenoprotein, and the only extracellular GPx of a family of oxidoreductases that catalyze the detoxification of hydro- and soluble lipid hydroperoxides by reduced glutathione. In addition to summarizing the biochemical function, regulation, and disease associations of GPx3, we specifically discuss the role and regulation of systemic and tumor cell expressed GPx3 in cancer. From this it is evident that GPx3 has a dichotomous role in different tumor types, acting as both a tumor suppressor and pro-survival protein. Further studies are needed to examine how loss or gain of GPx3 specifically affects oxidant scavenging and redox signaling in the extracellular tumor microenvironment, and how GPx3 might be targeted for therapeutic intervention.

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Section: Disease Association With Aberrant Gpx3mentioning

confidence: 99%

Section: Altered Gpx3 Expression and Role In Tumor Tissuesmentioning

confidence: 99%

Section: Altered Gpx3 Expression and Role In Tumor Tissuesmentioning

confidence: 99%

See 1 more Smart Citation

Extracellular Glutathione Peroxidase GPx3 and Its Role in Cancer

Chang

Worley

Phaëton

et al. 2020

Cancers

152

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“…Reports have shown that GPX-1 is crucially involved in the development and progression of colorectal cancer (8), thyroid cancer (9), and kidney cancer (10); meanwhile GPX-2 has been found to regulate invasion, metastasis, apoptosis, and prognosis in cancers including pancreatic cancer (11), bladder cancer (12), cervical cancer (13), and nasopharyngeal carcinoma (14), suggesting that GPX2 may be an oncogene. Furthermore, GPX-3 methylation has been linked to multiple cancers, has potential value in predicting prognosis (15)(16)(17), and is also considered to be a tumor suppressor (18)(19)(20)(21). GPX-4 regulates ferroptotic cancer cell death, and is related to the therapy resistance of cancer cells (22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

Identification the prognostic value of glutathione peroxidases expression levels in acute myeloid leukemia

Wei¹,

Xie²,

Liu³

et al. 2020

Ann Transl Med

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Background: Glutathione peroxidases (GPXs) are an enzyme family with peroxidase activity. Abnormal GPX expression is associated with carcinogenesis. However, the potential role of the GPX gene family in acute myeloid leukemia (AML) remains to be comprehensively examined. Methods:We analyzed GPX mRNA expression levels and determined the correlation between gene expression and the prognostic value via multiple universally acknowledged databases including the Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), PROGgeneV2, UALCAN, Cancer Cell Line Encyclopedia (CCLE), and The European Bioinformatics Institute (EMBL-EBI) databases. The functional network of differentially expressed GPXs was investigated via the NetworkAnalyst platform.Correlated genes as well as kinase, microRNA (miRNA), and transcription factor (TF) targets were identified using LinkedOmics. Results:We observed that the transcriptional expression levels of GPX-1, -2, -4, -7, and -8 had significant difference between AML patients samples and normal samples, and that AML patients with high expression of GPX-1, -3, -4, and -7 were associated with poorer prognosis of overall survival (OS). Functional enrichment analysis showed that the differentially expressed GPXs were mainly enriched in response to oxidative stress, regulation of immune response, and inflammatory response, along with glutathione metabolism and ferroptosis. Overexpression of correlated genes, PSMB10, VPS13D, NDUFS8, ATP5D, POLR2E, and HADH were linked to adverse OS in AML. Regulatory network analysis indicated that differentially expressed GPXs regulated cell proliferation, cancer progression, apoptosis, and cell cycle signaling via pathways involving cancer-related kinases (such as DAPK1 and SRC), miRNAs (such as miR-202 and miR-181), and TFs (such as SRF and E2F1).Conclusions: Our findings offer novel insights into the differential expression and prognostic potential of the GPX family in AML, and lay a foundation for subsequent research of GPX's role in the carcinogenesis and regulatory network of AML.

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“…Decreased levels of GPX3 are related to increased proliferation, motility, invasiveness, and poor prognosis [88]. Overexpression of GPX3 decreased the viability of melanoma cells and inhibited their growth in a xenografts model [89]. This data points to the important role of GPX3 inhibiting melanoma progression, and this subject should be more addressed in the field.…”

Section: Glutathione Systemmentioning

confidence: 95%

Redox-Related Proteins in Melanoma Progression

et al. 2022

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Melanoma is the most aggressive type of skin cancer. Despite the available therapies, the minimum residual disease is still refractory. Reactive oxygen and nitrogen species (ROS and RNS) play a dual role in melanoma, where redox imbalance is involved from initiation to metastasis and resistance. Redox proteins modulate the disease by controlling ROS/RNS levels in immune response, proliferation, invasion, and relapse. Chemotherapeutics such as BRAF and MEK inhibitors promote oxidative stress, but high ROS/RNS amounts with a robust antioxidant system allow cells to be adaptive and cooperate to non-toxic levels. These proteins could act as biomarkers and possible targets. By understanding the complex mechanisms involved in adaptation and searching for new targets to make cells more susceptible to treatment, the disease might be overcome. Therefore, exploring the role of redox-sensitive proteins and the modulation of redox homeostasis may provide clues to new therapies. This study analyzes information obtained from a public cohort of melanoma patients about the expression of redox-generating and detoxifying proteins in melanoma during the disease stages, genetic alterations, and overall patient survival status. According to our analysis, 66% of the isoforms presented differential expression on melanoma progression: NOS2, SOD1, NOX4, PRX3, PXDN and GPX1 are increased during melanoma progression, while CAT, GPX3, TXNIP, and PRX2 are decreased. Besides, the stage of the disease could influence the result as well. The levels of PRX1, PRX5 and PRX6 can be increased or decreased depending on the stage. We showed that all analyzed isoforms presented some genetic alteration on the gene, most of them (78%) for increased mRNA expression. Interestingly, 34% of all melanoma patients showed genetic alterations on TRX1, most for decreased mRNA expression. Additionally, 15% of the isoforms showed a significant reduction in overall patient survival status for an altered group (PRX3, PRX5, TR2, and GR) and the unaltered group (NOX4). Although no such specific antioxidant therapy is approved for melanoma yet, inhibitors or mimetics of these redox-sensitive proteins have achieved very promising results. We foresee that forthcoming investigations on the modulation of these proteins will bring significant advances for cancer therapy.

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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

Cited by 42 publications

References 45 publications

Extracellular Glutathione Peroxidase GPx3 and Its Role in Cancer

Extracellular Glutathione Peroxidase GPx3 and Its Role in Cancer

Identification the prognostic value of glutathione peroxidases expression levels in acute myeloid leukemia

Redox-Related Proteins in Melanoma Progression

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