Apoptosis induced by all‐trans retinoic acid in N‐acetylglucosaminyltransferase V repressed human hepatocarcinoma cells is mediated through endoplasmic reticulum stress

Xu, Yingying; Lu, Yi; Fan, Kun; Shen, Zhemin

doi:10.1002/jcb.21088

Cited by 14 publications

(17 citation statements)

References 24 publications

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“…We previously reported that 80 mM ATRA intensified ER stress that was triggered in GnT-V-AS/7721 cells [Xu et al, 2007]. Our present study confirmed these results, demonstrating a significant increase in the levels of GRP78/Bip, CHOP, and processed ATF6 proteins and that of spliced XBP1 mRNA.…”

Section: Discussionsupporting

confidence: 95%

“…We previously reported that ER stress was triggered in human hepatocarcinoma 7721 cells that were transfected with the antisense cDNA of GnT-V (GnT-V-AS/7721) [Fang et al, 2006] and that all-trans-retinoic acid (ATRA) intensified this ER stress, even inducing apoptosis in GnT-V-AS/7721 cells [Xu et al, 2007]. However, knowledge of the molecular basis of the ER stress is limited.…”

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confidence: 98%

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All‐trans‐retinoic acid intensifies endoplasmic reticulum stress in N‐acetylglucosaminyltransferase V repressed human hepatocarcinoma cells by perturbing homocysteine metabolism

Guan

Yang

et al. 2009

J of Cellular Biochemistry

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We previously reported that all-trans-retinoic acid (ATRA) induced apoptosis in N-acetylglucosaminyltransferase V (GnT-V) repressed human hepatocarcinoma 7721 (GnT-V-AS/7721) cells via endoplasmic reticulum (ER) stress. In addition to confirming these findings, we further found that ATRA repressed the expression of betaine-homocysteine methyltransferase (BHMT) and cystathionine-beta-synthase (CBS), which are key enzymes that are involved in homocysteine metabolism, increased the level of intracellular homocysteine, and decreased the glutathione (GSH) level in GnT-V-AS/7721 cells. To investigate the effect of ATRA on homocysteine metabolism, cells were challenged with exogenous homocysteine. In GnT-V-AS/7721 cells with ATRA treatment, a significant elevation of intracellular homocysteine levels suggests that ATRA perturbs homocysteine metabolism in GnT-V-AS/7721 cells and, therefore, sensitizes the cells to homocysteine-induced ER stress. An obvious increase in the levels of GRP78/Bip protein and spliced XBP1 mRNA were observed. Furthermore, we observed that ATRA blunted the homocysteine-induced increase of GSH only in GnT-V-AS/7721 cells. These results demonstrate that ATRA intensifies ER stress and induces apoptosis in GnT-V-AS/7721 cells by disturbing homocysteine metabolism through the down-regulation of CBS and BHMT, depleting the cellular GSH and, in turn, altering the cellular redox status. In addition, we showed that ATRA did not trigger ER stress, induce apoptosis, or affect homocysteine metabolism in L02 cells, which is a cell type that is derived from normal liver tissue. These results provide support for the hypothesis that ATRA is an anticancer agent.

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Section: Discussionsupporting

confidence: 95%

mentioning

confidence: 98%

All‐trans‐retinoic acid intensifies endoplasmic reticulum stress in N‐acetylglucosaminyltransferase V repressed human hepatocarcinoma cells by perturbing homocysteine metabolism

Guan

Yang

et al. 2009

J of Cellular Biochemistry

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“…The roles of GnT-V in the metastasis/invasion of various types of tumors are conflicting. Upregulated GnT-V activity has been reported in human colon cancer, hepatocarcinoma and breast cancer tissues (6)(7)(8)34). However, increased GnT-V activity has been found to be associated with favorable stages as well as favorable prognosis in non-small cell lung cancers, bladder carcinomas and neuroblastoma (9)(10)(11).…”

Section: Expression Of Invasion-related Factors In the Bgc823/gnt-v Cmentioning

confidence: 99%

“…However, the role of GnT-V in different cancers remains controversial. In the case of colon cancer and hepatocarcinoma, for instance, high GnT-V expression is associated with a poor prognosis (6)(7)(8). In contrast, low GnT-V levels are linked to a poor prognosis in lung, bladder carcinoma and neuroblastoma patients (9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of the GnT-V gene inhibits metastasis and invasion of BGC823 gastric cancer cells

et al. 2013

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Abstract. Metastatic and invasive potential is a barrier to the successful treatment of gastric cancer. N-acetylglucosaminyltransferase V (GnT-V), a key enzyme catalyzing the formation of 1,6 N-acetylglucosamine (GlcNAc), has been demonstrated to display a distinct function in different types of tumors. The aim of this study was to investigate the role of GnT-V in the invasive potential of BGC823 human gastric cancer cells in vitro and the possible underlying mechanism. GnT-V was downregulated in BGC823 cells by oligo-siRNA transfection. Cell proliferation and invasiveness were assessed by CCK-8 assay, TUNEL assay, scratch-wound assay as well as Transwell assay. The products of GnT-V, β1-6 branching of asparagine-linked oligosaccharides, were determined by L-PHA lectin blot analysis. The expression of EGFRs, E-cadherin/vimentin and MMP-2/MMP-9 was analyzed both at the mRNA and protein levels. The results showed that downregulation of GnT-V decreased proliferation and the metastatic/invasive potential of BGC823 cells. The expression of EGFRs, E-cadherin/vimentin and MMP-9, molecules related to cancer metastasis and invasion in various tumors, were influenced correspondingly. These findings suggest that downregulation of GnT-V inhibited cell metastasis and invasion of BGC823 cells via EGFR signaling-initiated EMT phenotype and MMP-9 expression. These results provide a novel mechanism to explain the role of GnT-V in cell metastasis and invasion.

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“…78 kDa glucose-regulated protein is essential for the differentiation of NB cells [9]. Moreover, it is known that 78 kDa glucose-regulated protein is also influenced by ATRA, but the effect appears to be strictly connected to cell origin, as ATRA downregulates 78 kDa glucose-regulated protein expression in foetal bovine chondrocytes [58] but upregulates its expression in hepatocarcinoma cells [59]. Stress-70 protein and protein disulfide-isomerase A3 have already been correlated with ATRA and differentiation, being overexpressed in NB cells following ATRA treatment [9], [10].…”

Section: Discussionmentioning

confidence: 99%

Identification of Phosphoproteins as Possible Differentiation Markers in All-Trans-Retinoic Acid-Treated Neuroblastoma Cells

Mandili

Marini

Carta³

et al. 2011

PLoS ONE

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BackgroundNeuroblastic tumors account for 9–10% of pediatric tumors and neuroblastoma (NB) is the first cause of death in pre-school age children. NB is classified in four stages, depending on the extent of spreading. A fifth type of NB, so-called stage 4S (S for special), includes patients with metastatic tumors but with an overall survival that approximates 75% at five years. In most of these cases, the tumor regresses spontaneously and regression is probably associated with delayed neuroblast cell differentiation.Methodology/Principal FindingsIn order to identify new early markers to follow and predict this process for diagnostic and therapeutics intents, we mimicked the differentiation process treating NB cell line SJ-NK-P with all-trans-retinoic acid (ATRA) at different times; therefore the cell proteomic pattern by mass spectrometry and the phosphoproteomic pattern by a 2-DE approach coupled with anti-phosphoserine and anti-phosphotyrosine western blotting were studied.Conclusions/SignificanceProteomic analysis identified only two proteins whose expression was significantly different in treated cells versus control cells: nucleoside diphosphate kinase A (NDKA) and reticulocalbin-1 (RCN1), which were both downregulated after 9 days of ATRA treatment. However, phosphoproteomic analysis identified 8 proteins that were differentially serine-phosphorylated and 3 that were differentially tyrosine-phosphorylated after ATRA treatment. All proteins were significantly regulated (at least 0.5-fold down-regulated). Our results suggest that differentially phosphorylated proteins could be considered as more promising markers of differentiation for NB than differentially expressed proteins.

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Apoptosis induced by all‐trans retinoic acid in N‐acetylglucosaminyltransferase V repressed human hepatocarcinoma cells is mediated through endoplasmic reticulum stress

Cited by 14 publications

References 24 publications

All‐trans‐retinoic acid intensifies endoplasmic reticulum stress in N‐acetylglucosaminyltransferase V repressed human hepatocarcinoma cells by perturbing homocysteine metabolism

All‐trans‐retinoic acid intensifies endoplasmic reticulum stress in N‐acetylglucosaminyltransferase V repressed human hepatocarcinoma cells by perturbing homocysteine metabolism

Downregulation of the GnT-V gene inhibits metastasis and invasion of BGC823 gastric cancer cells

Identification of Phosphoproteins as Possible Differentiation Markers in All-Trans-Retinoic Acid-Treated Neuroblastoma Cells

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