Blocking of N-acetylglucosaminyltransferase V induces cellular endoplasmic reticulum stress in human hepatocarcinoma 7721 cells

Fang, Huan; Huang, Wei; Xu, Ying; Shen, Zhemin; Wu, Chao; Qiao, Shou Yi; Xu, Yan; Liu, Yu; Chen, Hui Li

doi:10.1038/sj.cr.7310011

Cited by 9 publications

(8 citation statements)

References 44 publications

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“…In comparison of our previous study [Fang et al, 2006], we demonstrated that ER stress was triggered in GnT-V-AS/7721 cells, which was evidenced by the activation and upregulation of GRP78/Bip, CHOP, and XBP1. However, caspase-12, -9, and -3 were not activated, indicating that the ER stress in GnT-V-AS/ 7721 cells was chronic and there were no signals of apoptosis.…”

Section: Discussionmentioning

confidence: 64%

“…In this study, downregulation of GnT-V was observed in both mock and GnT-V-AS/7721 cells with ATRA treatment, indicating that ATRA at a concentration of 80 mM may exert a permissive function for downregulation of GnT-V. GnT-V, an important cancer-associated enzyme, is located in transGolgi apparatus and like other GlcNAc transferases, it regulates the branch formation in complex-type N-linked oligosaccharides. We previously reported that blocking of GnT-V in GnT-V-AS/7721 cells altered the processing mode of N-linked oligosaccharides and produced deficient glycoproteins, which caused the ER stress in GnT-V-AS/7721 cells [Fang et al, 2006]. We presently demonstrate that chronic ER stress but not apoptosis is induced in GnT-V-AS/7721 cells, whereas ATRA enhances the ER stress and induces the apoptosis of those cells.…”

Section: Discussionmentioning

confidence: 85%

“…We previously reported that ER stress was induced in human hepatocarcinoma 7721 cells transfected with antisense cDNA of N-acetylglucosaminyltransferase V (GnT-V-AS/7721) [Fang et al, 2006] and the GnT-V-AS/7721 cells were more susceptible to apoptosis induced by all-trans-retinoic acid (ATRA) [Guo et al, 1999]. In this study, we demonstrate that 80 mM ATRA enhances the ER stress triggered in GnT-V-AS/ 7721 cells and subsequently induces apoptosis, suggesting that ATRA-induced apoptosis in GnT-V-AS/7721 cells is mediated through ER stress.…”

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confidence: 99%

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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

Fan

et al. 2006

J of Cellular Biochemistry

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We previously demonstrated that endoplasmic reticulum (ER) stress was triggered in human hepatocarcinoma 7721 cells transfected with antisense cDNA of N-acetylglucosaminyltransferase V (GnT-V-AS/7721) which were more susceptible to apoptosis induced by all-trans retinoic acid (ATRA). In the present study, we report that ATRA-induced apoptosis in GnT-V-AS/7721 cells is mediated through ER stress. We show here that ER stress is enhanced in GnT-V-AS/7721 cells with 80 microM ATRA treatment for 24 h, which is evidenced by the increase of GRP78/Bip, C/EBP-homologous protein-10 (CHOP, also known as GADD153) and spliced XBP1. Additionally, activation of caspase-12, caspase-9, and -3 was detected, and apoptosis morphology was observed in GnT-V-AS/7721 cells with ATRA treatment. These results suggest that ATRA enhances the ER stress triggered in GnT-V-AS/7721 cells, which represents a novel mechanism of ATRA to induce apoptosis. We further observed that GnT-V was significantly repressed and the structure of N-glycans was changed in GnT-V-AS/7721 cells with 80 microM ATRA treatment for 24 h, suggesting that repression of GnT-V by ATRA causes the enhanced ER stress and ER stress-mediated apoptosis in GnT-V-AS/7721 cells.

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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 85%

mentioning

confidence: 99%

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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

Fan

et al. 2006

J of Cellular Biochemistry

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“…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.…”

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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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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“…The Gn-TV protein is highly expressed in neurotumor cells Ample literature evidence suggests that the Gn-TV protein is highly expressed only in cancer cells and suppression of this protein results in an inhibition of metastasis [27][28][29][30]. Our preliminary analysis showed that this protein is highly expressed in cancer cells, such as the metastatic human neuroblastoma (SH-SY5Y), mouse neuroblastoma (N18), human oligodendroglioma (HOG), proliferating (undifferentiated) HN2 cells, but not in normal mouse brain and human fibroblasts (Fig.…”

Section: Resultsmentioning

confidence: 99%

A genetic strategy involving a glycosyltransferase promoter and a lipid translocating enzyme to eliminate cancer cells

et al. 2009

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The most common therapeutic strategy for the treatment of cancer uses antimetabolites, which block uncontrolled division of cancer cells and kill them. However, such antimetabolites also kill normal cells, thus yielding detrimental side effects. This emphasizes the need for an alternative therapy, which would have little or no side effects. Our approach involves designing genetic means to alter surface lipid determinants that induce phagocytosis of cancer cells. The specific target of this strategy has been the enzyme activity termed aminophospholipid translocase (APLT) or flippase that causes translocation of phosphatidylserine (PS) from the outer to the inner leaflet of the plasma membrane in viable cells. Efforts to identify the enigmatic, plasma membrane APLT of mammalian cells have led investigators to some P-type ATPases, which have often proven to be the APLT of internal membranes rather than the plasma membrane. By measuring kinetic parameters for the plasma membrane APLT activity, we have shown that the P-type ATPase Atp8a1 is the plasma membrane APLT of the tumorigenic N18 cells, but not the non-tumorigenic HN2 (hippocampal neuron x N18) cells. Targeted knockdown of this enzyme causes PS externalization in the N18 cells, which would trigger phagocytic removal of these cells. But how would we specifically express the mutants or antisense Atp8a1 in the cancer cells? This has brought us to a glycosyltransferase, GnT-V, which is highly expressed in the transformed cells. By using the GnT-V promoter to drive a luciferase reporter gene we have demonstrated a dramatic increase in luciferase expression selectively in tumor cells. The described strategy could be tested for the removal of cancer cells without the use of antimetabolites that often kill normal cells.

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Blocking of N-acetylglucosaminyltransferase V induces cellular endoplasmic reticulum stress in human hepatocarcinoma 7721 cells

Cited by 9 publications

References 44 publications

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

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

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

A genetic strategy involving a glycosyltransferase promoter and a lipid translocating enzyme to eliminate cancer cells

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