Knockdown of GGCT inhibits cell proliferation and induces late apoptosis in human gastric cancer

Zhang, Wenjie; Chen, Lei; Xiang, Hua; Hu, Chunhua; Shi, Wei; Dong, Ping; Lv, Wenjie

doi:10.1186/s12858-016-0075-8

Cited by 24 publications

(21 citation statements)

References 18 publications

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“…Moreover, studies have shown that apoptotic resistance promote cell proliferation . Apoptotic event exists both in early apoptosis and late apoptosis of cell cycle duration; DNA double strand irreversibly breaks and loses its function in late phase apoptosis . We indicated that fractalkine's molecular function on late phase apoptosis is crucial for promoting cell proliferation in pancreatic cancer.…”

Section: Discussionmentioning

confidence: 90%

Fractalkine/CX3CR1 induces apoptosis resistance and proliferation through the activation of the AKT/NF‐κB cascade in pancreatic cancer cells

Wang

Cai

et al. 2017

Cell Biochemistry & Function

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Fractalkine (FKN, CX3CL1) is highly expressed in a majority of malignant solid tumours. Fractalkine is the only known ligand for CX3CR1. In this study, we performed an analysis to determine the effects of fractalkine/CX3CR1 on modulating apoptosis and explored the related mechanisms. The expression of fractalkine/CX3CR1 was detected by immunohistochemistry and western blotting. The levels of AKT/p-AKT, BCL-xl, and BCL-2 were detected by western blotting. Then, the effects of exogenous and endogenous fractalkine on the regulation of tumour apoptosis and proliferation were investigated. The mechanism of fractalkine/CX3CR1 on modulating apoptosis in cancer cells through the activation of AKT/NF-κB/p65 signals was evaluated. The effect of fractalkine on regulating cell cycle distribution was also tested. Fractalkine, AKT/p-AKT, and apoptotic regulatory proteins BCL-xl and BCL-2 were highly expressed in human pancreatic cancer tissues. In vitro, fractalkine/CX3CR1 promoted proliferation and mediated resistance to apoptosis in pancreatic cancer cells. The antiapoptotic effect of fractalkine was induced by the activation of AKT/NF-κB/p65 signalling in pancreatic cancer cells. The NF-κB/p65 contributes to promote the expressions of BCL-xl and BCL-2 and reduce caspase activity, thereby inhibiting apoptotic processes. Treatment with fractalkine resulted in the enrichment of pancreatic cancer cells in S phase with a concomitant decrease in the number of cells in G1 phase. The present study demonstrated the function of fractalkine in the activation of the AKT/NF-κB/p65 signalling cascade and mediation of apoptosis resistance in pancreatic cancer cells. Fractalkine/CX3CR1 could serve as a diagnostic marker and as a potential target for chemotherapy in early stage pancreatic cancer. Pancreatic cancer is characterized by local recurrence, neural invasion, or distant metastasis. The present study demonstrated the overexpression of fractalkine/CX3CR1 in pancreatic cancer tissues, indicating its important role in the tumourigenesis of pancreatic cancer, and suggested that the overexpression of fractalkine/CX3CR1 could serve as a diagnostic marker for pancreatic cancer. Moreover, we reveal the mechanism that fractalkine functions on the activation of the AKT/NF-κB/p65 signalling cascade and regulation of the antiapoptosis process in pancreatic cancer cells. Fractalkine/CX3CR1 could serve as an effective therapeutic target of chemotherapeutic and biologic agents in early stage pancreatic cancer.

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Section: Discussionmentioning

confidence: 90%

Fractalkine/CX3CR1 induces apoptosis resistance and proliferation through the activation of the AKT/NF‐κB cascade in pancreatic cancer cells

Wang

Cai

et al. 2017

Cell Biochemistry & Function

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“…Ggct is an enzyme that plays a role in glutathione degradation (Oakley et al, 2008 ) and has been shown to be a contributor to a variety of cancers (reviewed in Zhang et al, 2016 ). Importantly, Ggct has been recently shown to play a role in cell proliferation and death, implicated by Ggct knockdown experiments that resulted in an inhibition of proliferation and an induction of apoptosis in human cancer cells (Zhang et al, 2016 ). Ggct has no known role in retinal development, but it is present in the developing and mature retina where it is most heavily distributed to the IPL and outer portion of the INL, where the RBC population is present (Figure 3 ).…”

Section: Resultsmentioning

confidence: 99%

“…The mechanism by which Ggct could alter RBC number remains unknown. Ggct is upregulated in many human cancers and therefore has been postulated to modulate both apoptotic and cell proliferation pathways (Zhang et al, 2016 ). For example, when GGCT was silenced in cultured colorectal cancer cells, it was sufficient to trigger caspase-3-mediated apoptosis (Zhang et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

“…Ggct is upregulated in many human cancers and therefore has been postulated to modulate both apoptotic and cell proliferation pathways (Zhang et al, 2016 ). For example, when GGCT was silenced in cultured colorectal cancer cells, it was sufficient to trigger caspase-3-mediated apoptosis (Zhang et al, 2016 ). Furthermore, it is known that decreased levels of intracellular glutathione are associated with cell death and given that Ggct is a key player in the glutathione degradation pathway, this further supports the postulation that Ggct may be influencing cell number, either directly or indirectly, by modulating the frequency of cell death during development (Cooper and Kristal, 1997 ).…”

Section: Discussionmentioning

confidence: 99%

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Genetic Control of Rod Bipolar Cell Number in the Mouse Retina

et al. 2018

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Genetic variants modulate the numbers of various retinal cell types in mice. For instance, there is minimal variation in the number of rod bipolar cells (RBCs) in two inbred strains of mice (A/J and C57BL/6J), yet their F1 offspring contain significantly more RBCs than either parental strain. To investigate the genetic source of this variation, we mapped the variation in the number of RBCs across 24 genetically distinct recombinant inbred (RI) strains (the AXB/BXA strain-set), seeking to identify quantitative trait loci (QTL). We then sought to identify candidate genes and potential casual variants at those genomic loci. Variation in RBC number mapped to three genomic loci, each modulating cell number in excess of one-third of the range observed across the RI strains. At each of these loci, we identified candidate genes containing variants that might alter gene function or expression. The latter genes were also analyzed using a transcriptome database, revealing a subset for which expression correlated with variation in RBC number. Using an electroporation strategy, we demonstrate that early postnatal expression of one of them, Ggct (gamma-glutamyl cyclotransferase), modulates bipolar cell number. We identify candidate regulatory variants for this gene, finding a large structural variant (SV) in the putative promoter that reduces expression using a luciferase assay. This SV reducing Ggct expression in vitro is likely the causal variant within the gene associated with the variation in Ggct expression in vivo, implicating it as a quantitative trait variant (QTV) participating in the control of RBC number.

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“…NF-Y and Sp1 bind to the CCAAT boxes and to the GC box, respectively, to positively regulate transcription of the GGCT gene. Since promoters with several NF-Y-binding CCAAT boxes were found in genes related to the cell cycle, Ohno et al suggested that GGCT may also play a role in the cell cycle [ 18 ], as confirmed by other studies [ 19 , 20 , 21 , 22 ].…”

Section: Molecular Regulation Mechanism Of Ggct Expression In Cancmentioning

confidence: 86%

Mechanisms of Tumor Growth Inhibition by Depletion of γ-Glutamylcyclotransferase (GGCT): A Novel Molecular Target for Anticancer Therapy

Kageyama

Hiromi

Taniguchi

et al. 2018

IJMS

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γ-Glutamylcyclotransferase (GGCT), which is one of the major enzymes involved in glutathione metabolism, is upregulated in a wide range of cancers—glioma, breast, lung, esophageal, gastric, colorectal, urinary bladder, prostate, cervical, ovarian cancers and osteosarcoma—and promotes cancer progression; its depletion leads to the suppression of proliferation, invasion, and migration of cancer cells. It has been demonstrated that the suppression or inhibition of GGCT has an antitumor effect in cancer-bearing xenograft mice. Based on these observations, GGCT is now recognized as a promising therapeutic target in various cancers. This review summarizes recent advances on the mechanisms of the antitumor activity of GGCT inhibition.

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Knockdown of GGCT inhibits cell proliferation and induces late apoptosis in human gastric cancer

Cited by 24 publications

References 18 publications

Fractalkine/CX3CR1 induces apoptosis resistance and proliferation through the activation of the AKT/NF‐κB cascade in pancreatic cancer cells

Fractalkine/CX3CR1 induces apoptosis resistance and proliferation through the activation of the AKT/NF‐κB cascade in pancreatic cancer cells

Genetic Control of Rod Bipolar Cell Number in the Mouse Retina

Mechanisms of Tumor Growth Inhibition by Depletion of γ-Glutamylcyclotransferase (GGCT): A Novel Molecular Target for Anticancer Therapy

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