Diminished COX-2/PGE2-Mediated Antiviral Response Due to Impaired NOX/MAPK Signaling in G6PD-Knockdown Lung Epithelial Cells

Lin, Hsin Ru; Wu, Yi; Yen, Wei Chen; Yang, Che‐Hua; Chiu, Daniel

doi:10.1371/journal.pone.0153462

Cited by 21 publications

(25 citation statements)

References 54 publications

(67 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The results from the present study and from previous studies suggested that G6PD may promote ROS production in RCC cells (16,49). Previous studies also reported a possible interaction between G6PD expression and the MAPK signaling pathway (59,60).…”

Section: Discussionsupporting

confidence: 80%

G6PD facilitates clear cell renal cell carcinoma invasion by enhancing MMP2 expression through ROS‑MAPK axis pathway

et al. 2020

View full text Add to dashboard Cite

Glucose-6-phosphate dehydrogenase (G6PD) is crucial rate-limiting enzyme of the pentose phosphate pathway (PPP). G6PD dysregulation has been reported in various types of human cancer, and the role of G6PD in cancer progression was demonstrated in numerous studies. A previous study from our laboratory described the prognostic significance of G6PD in clear cell renal cell carcinoma (ccRCC), and demonstrated its proliferative role through positive feedback regulation of the phosphorylated form of signal transducer and activator of transcription 3. However, the role of G6PD in ccRCC invasion remains unclear. In the present study, reverse transcription-quantitative (RT-q) PCR, western blotting, enzyme activity assay, transwell assay and immunohistochemistry analysis in cell model, xenograft mice model and human specimen studies were performed to evaluate the role of G6PD in ccRCC invasion. The results from the present study demonstrated that G6PD may promote ccRCC cell invasive ability by increasing matrix metalloproteinase 2 (MMP2) mRNA and protein expression both in vitro and in vivo. In addition, a positive correlation between G6PD and MMP2 expression was demonstrated by RT-qPCR and western blotting in twenty pairs of ccRCC tumor specimens and matched adjacent normal tissues. Furthermore, G6PD promoted reactive oxygen species (ROS) generation and activated the MAPK signaling pathway in ccRCC cells. In addition, ROS significantly promoted the MAPK signaling pathway activation, which in turn contributed to MMP2 overexpression in ccRCC cells. In conclusion, the present study demonstrated that G6PD may facilitate ccRCC cell invasive ability by enhancing MMP2 expression through ROS-MAPK axis pathway.

show abstract

Section: Discussionsupporting

confidence: 80%

G6PD facilitates clear cell renal cell carcinoma invasion by enhancing MMP2 expression through ROS‑MAPK axis pathway

et al. 2020

View full text Add to dashboard Cite

show abstract

“…It has been reported that, G6PD plays important roles in the regulation of reactive oxygen species (ROS) generation [ 1 ]. As the PPP is activated, G6PD is usually considered the pacesetter for nicotinamide adenine dinucleotide phosphate (NADPH) production in cancer cells [ 1 , 2 , 13 ]. NADPH is a substrate of NADPH oxidases and functionally important hydrogen donor that serves as a cofactor in anabolic reactions of fatty acids, isoprenoids, and aromatic amino acids synthesis [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

“…NOX4, especially the membrane-bound NOX4, plays a major role in regulating cellular functions and is thought to be an electron transporter [ 13 , 15 , 21 ]. In combination with NADPH, NOX4 could pass the electrons to an electron acceptor according to the equation NADPH→FAD→Heme→O 2 to generate O 2 -.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

G6PD promotes renal cell carcinoma proliferation through positive feedback regulation of p-STAT3

et al. 2017

View full text Add to dashboard Cite

Ectopic Glucose 6-phosphate dehydrogenase (G6PD) expression plays important role in tumor cell metabolic reprogramming and results in poor prognosis of multiple malignancies. Our previous study indicated that G6PD is overexpressed in clear cell renal cell carcinoma (ccRCC), the most common subtype of RCC. However, its role in RCC is still unclear. Here, we demonstrate that G6PD is not only up-regulated in all types of RCC specimens but also displays higher activities in RCC cell lines. G6PD overexpression promoted RCC cell proliferation, altered cell cycle distribution, and enhanced xenografted RCC development. G6PD up-regulated ROS generation by facilitating NADPH-dependent NOX4 activation, which led to increased expression of p-STAT3 and CyclinD1. Enhanced ROS generation rescued the p-STAT3 and CyclinD1 expression reduction in G6PD-knockdown cells, while ROS scavengers reversed the up-regulated p-STAT3 and CyclinD1 expression in G6PD-overexpressing cells. Furthermore, p-STAT3 activated G6PD gene expression via binding to the G6PD promoter, demonstrating that p-STAT3 forms a positive feedback regulatory loop for G6PD overexpression. G6PD expression was up or down-regulated in response to the impact of p-STAT3 activators or inhibitors. Therefore, G6PD may be an effective RCC therapeutic target.

show abstract

“…G6PD modulates xenobiotic metabolism via the Nrf2 signaling pathway and affects the xenobiotic metabolizing enzyme expression 5 . Moreover, it acts as a key regulator of the cellular inflammatory and immune response against viral infection 6 , 7 . Because G6PD is a rate-limiting enzyme in the pentose-phosphate shunt, it is essential for regulating energy consumption and glucose metabolism 8 .…”

Section: Introductionmentioning

confidence: 99%

Glucose-6-phosphate dehydrogenase is indispensable in embryonic development by modulation of epithelial-mesenchymal transition via the NOX/Smad3/miR-200b axis

Lee

Shih

et al. 2018

Cell Death Dis

Self Cite

View full text Add to dashboard Cite

Glucose-6-phosphate dehydrogenase (G6PD) is a housekeeping enzyme involved in the pentose phosphate shunt for producing nicotinamide adenine dinucleotide phosphate (NADPH). Severe G6PD deficiency leads to embryonic lethality, but the underlying mechanism is unclear. In the current study, the effects of G6PD on epithelial–mesenchymal transition (EMT), especially during embryonic development, were investigated. The knockdown of G6PD induced morphological changes, accompanied by the suppression of epithelial markers, E-cadherin and β-catenin, in A549 and MDCK cells. Such modulation of EMT was corroborated by the enhancement of migration ability in G6PD-knockdown A549 cells. Zebrafish embryos with g6pd knockdown exhibited downregulation of the E-cadherin/β-catenin adhesion molecules and impaired embryonic development through reduction in epiboly rate and increase in cell shedding at the embryo surface. The dysregulation in zebrafish embryonic development caused by g6pd knockdown could be rescued through human G6PD or CDH1 (E-cadherin gene) cRNA coinjection. The Smad3/miR-200b axis was dysregulated upon G6PD knockdown, and the reconstitution of SMAD3 in G6PD-knockdown A549 cells restored the expression of E-cadherin/β-catenin. The inhibition of NADPH oxidase (NOX) activation through the loss of p22phox signaling was involved in the dysregulation of the Smad3/miR-200b axis upon G6PD knockdown. The reconstitution of G6PD led to the recovery of the regulation of NOX/Smad3/miR-200b signaling and increased the expression of E-cadherin/β-catenin in G6PD-knockdown cells. Thus, these results suggest that in the EMT process, G6PD plays an important regulatory role as an integral component of the NOX/Smad3/miR-200b axis.

show abstract

Diminished COX-2/PGE2-Mediated Antiviral Response Due to Impaired NOX/MAPK Signaling in G6PD-Knockdown Lung Epithelial Cells

Cited by 21 publications

References 54 publications

G6PD facilitates clear cell renal cell carcinoma invasion by enhancing MMP2 expression through ROS‑MAPK axis pathway

G6PD facilitates clear cell renal cell carcinoma invasion by enhancing MMP2 expression through ROS‑MAPK axis pathway

G6PD promotes renal cell carcinoma proliferation through positive feedback regulation of p-STAT3

Glucose-6-phosphate dehydrogenase is indispensable in embryonic development by modulation of epithelial-mesenchymal transition via the NOX/Smad3/miR-200b axis

Contact Info

Product

Resources

About