scholarly journals Inhibition of Glutamine Uptake Improves the Efficacy of Cetuximab on Gastric Cancer

2021 ◽  
Vol 20 ◽  
pp. 153473542110453
Author(s):  
Huanrong Ma ◽  
Jingjing Wu ◽  
Minyu Zhou ◽  
Jianhua Wu ◽  
Zhenzhen Wu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Gastric Carcinoma ◽  
Advanced Gastric Cancer ◽  
Inhibitory Effect ◽  
Carcinoma Cells ◽  
Phase Iii ◽  
Gastric Carcinoma Cell ◽  
Glutamine Uptake

Treatment for advanced gastric cancer is challenging. Epidermal growth factor receptor (EGFR) contributes to the proliferation and development of gastric cancer (GC), and its overexpression is associated with unfavorable prognosis in GC. Cetuximab, a monoclonal antibody targeting EGFR, failed to improve the overall survival of gastric cancer patients indicated in phase III randomized trials. Glutamine is a vital nutrient for tumor growth and its metabolism contributes to therapeutic resistance, making glutamine uptake an attractive target for cancer treatment. The aim of the present study was to investigate whether intervention of glutamine uptake could improve the effect of cetuximab on GC. The results of MTT assay showed that by glutamine deprivation or inhibition of glutamine uptake, the viability of gastric carcinoma cells was inhibited more severely than that of human immortal gastric mucosa epithelial cells (GES-1). The expression of the key glutamine transporter alanine-serine-cysteine (ASC) transporter 2 (ASCT2; SLC1A5) was significantly higher in gastric carcinoma tissues and various gastric carcinoma cell lines than in normal gastric tissues and cells, as shown by immunohistochemistry and western blotting, while silencing ASCT2 significantly inhibited the viability and proliferation of gastric carcinoma cells. Consistent with previous studies, it was shown herein by MTT and EdU assays that cetuximab had a weak inhibitory effect on the cell viability of gastric carcinoma cells. However, inhibiting glutamine uptake by blockade of ASCT2 with l-γ-glutamyl- p-nitroanilide (GPNA) significantly enhanced the inhibitory effect of cetuximab on suppressing the proliferation of gastric cancer both in vitro and in vivo. Moreover, combining cetuximab and GPNA induced cell apoptosis considerably in gastric carcinoma cells, as shown by flow cytometry, and had a higher depressing effect on gastric cancer proliferation both in vitro and in vivo, as compared to either treatment alone. The present study suggested that inhibition of glutamine uptake may be a promising strategy for improving the inhibitory efficacy of cetuximab on advanced gastric cancer.

scholarly journals Sulforaphane suppresses autophagy during the malignant progression of gastric carcinoma via activating miR-4521/PIK3R3 pathway

2021 ◽  
pp. 096032712110544
Author(s):  
Zi-tan Peng ◽  
Pei Gu
Keyword(s):  
Cell Proliferation ◽  
Gastric Carcinoma ◽  
Carcinoma Cells ◽  
Malignant Progression ◽  
Gastric Carcinoma Cell ◽  
Over Expression ◽  
Anti Cancer ◽  
Underlying Mechanisms ◽  
Cruciferous Plants

Objective Sulforaphane, which exerts an effective anti-cancer ability, is a phytochemical converted from cruciferous plants. Here, we aimed to identify whether sulforaphane could suppress autophagy during the malignant progression of gastric carcinoma and to explore the underlying mechanisms. Methods SGC7901 cells were transfected with miR-4521 mimics, inhibitor, and pcDNA3.1- PIK3R3, and treated with sulforaphane or autophagy inhibitor. Cell proliferation, apoptosis, and miR-4521 or PIK3R3 expression were detected. Results MiR-4521 over-expression suppressed LC3-II/I ratio and Beclin-1 expression but induced p62 expression in SGC7901 cells. MiR-4521 also reduced gastric carcinoma cell proliferation and promoted apoptosis in vitro. In the mechanical observation, we identified that miR-4521 directly targeted PIK3R3 to repress its expression, and PIK3R3 up-regulation partly antagonized miR-4521-mediated autophagy, proliferation, and apoptosis in gastric carcinoma cells. In addition, sulforaphane exerted effective anti-cancer functions by repressing autophagy and growth in tumor cells at a concentration-dependent way. MiR-4521 inhibition or PIK3R3 over-expression weakened the anti-cancer functions of sulforaphane in gastric carcinoma cells. Conclusion Consequently, miR-4521 suppressed autophagy during the malignant progression of gastric carcinoma by targeting PIK3R3. Thus, miR-4521 may be applied as a therapeutic target for sulforaphane in gastric carcinoma.

scholarly journals Adenovirus-mediated ING4 expression reduces multidrug resistance of human gastric carcinoma cells in vitro and in vivo

2013 ◽  
Vol 30 (5) ◽  
pp. 2187-2194 ◽  
Author(s):  
ZONG-LEI MAO ◽  
SONG-BING HE ◽  
WEI-HUA SHENG ◽  
XIAO-QIANG DONG ◽  
JI-CHENG YANG
Keyword(s):  
Multidrug Resistance ◽  
Gastric Carcinoma ◽  
Carcinoma Cells ◽  
Human Gastric Carcinoma ◽  
Human Gastric Carcinoma Cells

scholarly journals N6-(2-hydroxyethyl)-Adenosine Induces Apoptosis via ER Stress and Autophagy of Gastric Carcinoma Cells In Vitro and In Vivo

2020 ◽  
Vol 21 (16) ◽  
pp. 5815
Author(s):  
Hongqing Xie ◽  
Xiaotong Li ◽  
Weiwei Yang ◽  
Liping Yu ◽  
Xiasen Jiang ◽  
...  
Keyword(s):  
Gastric Carcinoma ◽  
Er Stress ◽  
Carcinoma Cells ◽  
Dependent Manner ◽  
Antineoplastic Effect ◽  
Tumor Tissues ◽  
Induced Apoptosis ◽  
Species Production

Gastric cancer is the most common malignant tumor of the digestive tract and is great challenge in clinical treatment. N6-(2-Hydroxyethyl)-adenosine (HEA), widely present in various fungi, is a natural adenosine derivative with many biological and pharmacological activities. Here, we assessed the antineoplastic effect of HEA on gastric carcinoma. HEA exerted cytotoxic effects against gastric carcinoma cells (SGC-7901 and AGS) in a dose and time-dependent manner. Additionally, we found that HEA induced reactive oxygen species production and mitochondrial membrane potential depolarization. Moreover, it could trigger caspase-dependent apoptosis, promoting intracellular Ca2+-related endoplasmic reticulum (ER) stress and autophagy. On the other hand, HEA could significantly inhibit the growth of transplanted tumors in nude mice and induce apoptosis of tumor tissues cells in vivo. In conclusion, HEA induced apoptosis of gastric carcinoma cells in vitro and in vivo, demonstrating that HEA is a potential chemotherapeutic agent for gastric carcinoma.

scholarly journals Periplocin Extracted from Cortex Periplocae Induced Apoptosis of Gastric Cancer Cells via the ERK1/2-EGR1 Pathway

2016 ◽  
Vol 38 (5) ◽  
pp. 1939-1951 ◽  
Author(s):  
Lei Li ◽  
Lian-Mei Zhao ◽  
Su-li Dai ◽  
Wen-Xuan Cui ◽  
Hui-Lai Lv ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Viability ◽  
Cancer Cells ◽  
Inhibitory Effect ◽  
Tunel Staining ◽  
Dependent Manner ◽  
Gastric Cancer Cells ◽  
Induced Apoptosis

Background/Aims: Periplocin is extracted from the traditional herbal medicine cortex periplocae, which has been reported to suppress the growth of cancer cells. However, little is known about its effect on gastric cancer cells. Methods: Gastric cancer cells were treated with periplocin, and cell viability was assessed using MTS assay. Flow cytometry and TUNEL staining were performed to evaluate apoptosis, and protein expression was examined by western blotting. Microarray analysis was used to screen for changes in related genes. Results: We found that periplocin had an inhibitory effect on gastric cancer cell viability in a dose-dependent manner. Periplocin inhibited cell viability via the ERK1/2-EGR1 pathway to induce apoptosis. Periplocin also inhibited the growth of tumor xenografts and induced apoptosis in vivo. Conclusion: Our results show that periplocin inhibits the proliferation of gastric cancer cells and induces apoptosis in vitro and in vivo, indicating its potential to be used as an antitumor drug.

scholarly journals Investigation and Identification of let-7a Related Functional Proteins in Gastric Carcinoma by Proteomics

2012 ◽  
Vol 35 (4) ◽  
pp. 285-295 ◽  
Author(s):  
Yimin Zhu ◽  
Xingyuan Xiao ◽  
Lairong Dong ◽  
Zhiming Liu
Keyword(s):  
Gastric Carcinoma ◽  
Noncoding Rna ◽  
Target Genes ◽  
Rho Gtpase ◽  
Two Dimensional Gel Electrophoresis ◽  
Gastric Carcinoma Cell ◽  
Rna Molecules ◽  
Small Noncoding Rna

MicroRNAs are small noncoding RNA molecules that control expression of target genes. Our previous studies show that let-7a decreased in gastric carcinoma and that up-regulation of let-7a by gene augmentation inhibited gastric carcinoma cell growth bothin vitroandin vivo, whereas it remains largely unclear as to how let-7a affects tumor growth. In this study, proteins associated with the function of let-7a were detected by high throughout screening. The cell line of SGC-7901 stablely overexpressing let-7a was successfully established by gene cloning. Two-dimensional gel electrophoresis (2-DEy was used to separate the total proteins of SGC-7901/let-7a, SGC-7901/EV and SGC-7901, and PDQuest software was applied to analyze 2-DE images. Ten different protein spots were identified by MALDI-TOF-MS, and they may be the proteins associated with let-7a function. The overexpressed proteins included Antioxidant protein 2, Insulin–like growth factor binding protein 2, Protein disulfide isomerase A2, C-1-tetrahydrofolate synthase, Cyclin-dependent kinase inhibitor1 (CDKN1) and Rho–GTPase activating protein 4. The underexpressed proteins consisted of S-phase kinase-associated protein 2 (Spk2), Platelet membrane glycoprotein, Fibronectin and Cks1 protein. Furthermore, the different expression levels of the partial proteins (CDKN1, Spk2 and Fibronectin) were confirmed by western blot analysis. The data suggest that these differential proteins are involved in a novel let-7a signal pathway and these findings provide the basis to investigate the functional mechanisms of let-7a in gastric carcinoma.

scholarly journals Effect of Non-Anticoagulant N-Desulfated Heparin on Basic Fibroblast Growth Factor Expression, Angiogenesis, and Metastasis of Gastric Carcinoma In Vitro and In Vivo

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Jin-Lian Chen ◽  
Jing Fan ◽  
Ming-Xiang Chen ◽  
Ying Dong ◽  
Jian-Zhong Gu
Keyword(s):  
Gastric Cancer ◽  
Growth Factor ◽  
Gastric Carcinoma ◽  
Normal Saline ◽  
Saline Group ◽  
Fibroblast Growth ◽  
Normal Saline Group ◽  
Heparin Group

Objective. The present study was performed to investigate the effect of N-desulfated heparin on basic fibroblast growth factor (bFGF) expression, tumor angiogenesis and metastasis of gastric carcinoma.Methods. Human gastric cancer SGC-7901 tissues were orthotopically implanted into the stomach of NOD SCID mice. Twenty mice were randomly divided into two groups which received either intravenous injection of 0.9% NaCl solution (normal saline group) or 10 mg/kg N-desulfated heparin (N-desulfated heparin group) twice weekly for three weeks. In vitro, human gastric carcinoma SGC-7901 cells were treated with N-desulfated heparin in different concentration (0.1 mg/mL, 1 mg/mL, N-desulfated heparin group), and treated with medium (control group).Results. In vivo, the tumor metastasis rates were 9/10 in normal saline group and 2/10 in N-desulfated heparin group (P<0.05). The intratumoral microvessel density was higher in normal saline group than in N-desulfated heparin group (P<0.05). bFGF expression in gastric tissue was inhibited by N-desulfated heparin (P<0.05). There was no bleeding in N-desulfated heparin group. In vitro, N-desulfated heparin inhibited significantly bFGF protein and mRNA expression of gastric carcinoma cells (P<0.05).Conclusions. N-desulfated heparin can inhibit the metastasis of gastric cancer through inhibiting tumor bFGF expression and tumor angiogenesis with no obvious anticoagulant activity.

scholarly journals YTHDF2 Inhibits Gastric Cancer Cell Growth by Regulating FOXC2 Signaling Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Xudong Shen ◽  
Kui Zhao ◽  
Liming Xu ◽  
Guilian Cheng ◽  
Jianhong Zhu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Patient ◽  
Signaling Pathway ◽  
Inhibitory Effect ◽  
Signal Pathways ◽  
Gastric Cancer Cells ◽  
Cancer Cell Growth ◽  
Patient Prognosis

BackgroundGastric cancer (GC) is one of the most common malignancies in the world, and the fourth most frequent malignancy worldwide. YTHDF2 (YTH domain family 2, YTHDF2) binds to mRNA containing m6A, thereby regulating the localization and stability of the bound mRNA. YTHDF2 was shown to be associated with some cancer patient prognosis. However, the effect of YTHDF2 on gastric cancer and the molecular mechanism of this effect have not been documented.MethodsTo conduct this research, YTHDF2 expression levels in public databases and gastric cancer patient samples were analyzed. The effects of YTHDF2 on the growth of gastric cancer cells were detected in vivo and in vitro. RNA-seq was used to analyze the signal pathways regulated by YTHDF2, and experiments were carried out for verification.ResultsIn our study, we found that YTHDF2 has lower expression in GC tissues and GC cells, and inhibits the growth of GC cells. In addition, the analysis of clinical data found that the expression level of YTHDF2 is closely related to the stage of GC and the survival of patients with GC. RNA sequencing results showed that overexpression of YTHDF2 significantly reduced protein expression in the FOXC2 (Forkhead box protein C2, FOXC2) signaling pathway. Finally, we found that knockout of FOXC2 reversed the inhibitory effect of YTHDF2 on GC cells.ConclusionIn summary, YTHDF2 inhibits the growth of GC cells by negatively regulating FOXC2 and may serve as a prognostic marker in GC.

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