MDR-1, Bcl-xL, H. pylori, and Wnt/β-catenin signalling in the adult stomach: how much is too much?

Macleod, John

doi:10.1038/labinvest.2012.151

Cited by 6 publications

(4 citation statements)

References 28 publications

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“…In gastric cancers, MDR-1 behaves as an oncofetal protein and had anti-apoptotic action through cross-talk with Bcl-xL [ 28 ]. Basically, MDR-1, Bcl-xL, H. pylori , and Wnt/β-catenin signaling contribute to gastric carcinogenesis [ 29 ]. β-catenin-transduced regulatory T cells showed decreases in c-myc and Bax but an increase in Bcl-xL [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

An increase in glucosylceramide synthase induces Bcl-xL-mediated cell survival in vinorelbine-resistant lung adenocarcinoma cells

Chiu

et al. 2015

Oncotarget

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Reversing drug resistance with concurrent treatment confers anticancer benefits. In this study, we investigated the potential mechanism of glucosylceramide synthase (GCS)-mediated vinca alkaloid vinorelbine (VNR) resistance in human lung adenocarcinoma cells. Compared with PC14PE6/AS2 (AS2) and CL1-0 cells, apoptotic analysis showed that both A549 and CL1-5 cells were VNR-resistant, while these cells highly expressed GCS at the protein level. VNR treatment significantly converts ceramide to glucosylceramide in VNR-resistant cells; however, pharmacologically inhibiting GCS with (±)-threo-1-Phenyl-2-decanoylamino-3-morpholino-1-propanol hydrochloride (PDMP) induced ceramide accumulation, accompanied by a decrease in glucosylceramide. Under concurrent treatment with VNR and PDMP, an increase in cell apoptosis could be identified; furthermore, genetically silencing GCS confirmed these effects. In VNR-resistant cells, Bcl-xL expression was aberrantly increased, while pharmacologically inhibiting Bcl-xL with ABT-737 sensitized cells to VNR-induced apoptosis. Conversely, enforced expression of Bcl-xL strengthened the survival response of the VNR-susceptible cells AS2 and CL1-0. Without changes in mRNA expression, Bcl-xL was overexpressed independent of β-catenin-mediated transcriptional regulation in VNR-resistant cells. Simultaneous GCS inhibition and VNR treatment caused a decrease in Bcl-xL expression. According to these findings, an increase in GCS caused Bcl-xL augmentation, facilitating VNR resistance in lung adenocarcinoma cells.

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Section: Introductionmentioning

confidence: 99%

An increase in glucosylceramide synthase induces Bcl-xL-mediated cell survival in vinorelbine-resistant lung adenocarcinoma cells

Chiu

et al. 2015

Oncotarget

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“…In the nucleus, β -catenin binds to TCF family and serves as a transcriptional regulator [10, 11]. Recent study showed that H. pylori infection stimulates release of β -catenin which in turn is translocated into nucleus [12]. Nuclear translocation of β -catenin and cell proliferation have been related to c-myc in H .…”

Section: Introductionmentioning

confidence: 99%

α-Lipoic Acid InhibitsHelicobacter pylori-Induced Oncogene Expression and Hyperproliferation by Suppressing the Activation of NADPH Oxidase in Gastric Epithelial Cells

Byun

Lim

Kim

et al. 2014

Mediators of Inflammation

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Hyperproliferation and oncogene expression are observed in the mucosa of Helicobacter pylori- (H. pylori-) infected patients with gastritis or adenocarcinoma. Expression of oncogenes such as β-catenin and c-myc is related to oxidative stress. α-Lipoic acid (α-LA), a naturally occurring thiol compound, acts as an antioxidant and has an anticancer effect. The aim of this study is to investigate the effect of α-LA on H. pylori-induced hyperproliferation and oncogene expression in gastric epithelial AGS cells by determining cell proliferation (viable cell numbers, thymidine incorporation), levels of reactive oxygen species (ROS), NADPH oxidase activation (enzyme activity, subcellular levels of NADPH oxidase subunits), activation of redox-sensitive transcription factors (NF-κB, AP-1), expression of oncogenes (β-catenin, c-myc), and nuclear localization of β-catenin. Furthermore, we examined whether NADPH oxidase mediates oncogene expression and hyperproliferation in H. pylori-infected AGS cells using treatment of diphenyleneiodonium (DPI), an inhibitor of NADPH oxidase. As a result, α-LA inhibited the activation of NADPH oxidase and, thus, reduced ROS production, resulting in inhibition on activation of NF-κB and AP-1, induction of oncogenes, nuclear translocation of β-catenin, and hyperproliferation in H. pylori-infected AGS cells. DPI inhibited H. pylori-induced activation of NF-κB and AP-1, oncogene expression and hyperproliferation by reducing ROS levels in AGS cells. In conclusion, we propose that inhibiting NADPH oxidase by α-LA could prevent oncogene expression and hyperproliferation occurring in H. pylori-infected gastric epithelial cells.

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“…At present, although the roles of H. pylori infection and Wnt/β-catenin in the development and metastasis of GC have been independently studied (Macleod RJ, 2012;Neal JT, et al, 2013), the association between H. pylori infection and Wnt/β-catenin in the development and progression of gastric carcinoma remains to be clarified (Ilyas, 2005;McMillan et al, 2005). Thus, it is essential to simultaneously examine H. pylori infection and the expression of E-cadherin, β-catenin and TCF4 proteins, and their association in various gastric mucosal lesions, thereby providing an additional theoretical basis on GC tumorigenesis and progression.…”

Section: Discussionmentioning

confidence: 99%

Expression of the E-cadherin/β-catenin/tcf-4 Pathway in Gastric Diseases with Relation to Helicobacter pylori Infection: Clinical and Pathological Implications

Yu¹,

Xu²,

Xu³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Objective: To determine the expression of E-cadherin, β-catenin, and transcription factor 4 (TCF4) proteins in gastric diseases with relation to Helicobacter pylori infection. Methods: A total of 309 patients including 60 with superficial gastritis (SG), 57 with atrophic gastritis (AG) and 192 with gastric cancer (GC), were enrolled. The expression of E-cadherin, β-catenin, TCF4 proteins in the gastric mucosa was detected by immunohistochemistry and H. pylori infection by immunohistochemistry and PCR. Results: The expression rates of E-cadherin were significantly higher in SG and AG than in GC (P<0.01), while those of β-catenin in the nucleus were significantly lower in SG and AG than in GC (P<0.05). In GC cases, the expression rates of E-cadherin, β-catenin and TCF4 were significantly higher in the intestinal type than in the diffuse type (P<0.05). In GC patients, the expression rate of E-cadherin was significantly higher in the presence of H. pylori than in the absence of infection (P=0.011). Moreover, the expression level of TCF4 and β-catenin protein was significantly higher in the nucleus and cytoplasm in H. pylori positive than in H. pylori negative GC patients, especially in those with the intestinal type (all P < 0.05). Conclusion: The expression of E-cadherin and β-catenin progressively decreases during the process of GC tumorigenesis, while overexpression of TCF4 occurs. H. pylori infection is associated with a significant increase in the expression of E-cadherin and β-catenin in the cytoplasm and nucleus in GC patients, especially those with the intestinal type.

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MDR-1, Bcl-xL, H. pylori, and Wnt/β-catenin signalling in the adult stomach: how much is too much?

Cited by 6 publications

References 28 publications

An increase in glucosylceramide synthase induces Bcl-xL-mediated cell survival in vinorelbine-resistant lung adenocarcinoma cells

An increase in glucosylceramide synthase induces Bcl-xL-mediated cell survival in vinorelbine-resistant lung adenocarcinoma cells

α-Lipoic Acid InhibitsHelicobacter pylori-Induced Oncogene Expression and Hyperproliferation by Suppressing the Activation of NADPH Oxidase in Gastric Epithelial Cells

Expression of the E-cadherin/β-catenin/tcf-4 Pathway in Gastric Diseases with Relation to Helicobacter pylori Infection: Clinical and Pathological Implications

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