scholarly journals Autophagy Facilitates Metadherin-Induced Chemotherapy Resistance Through the AMPK/ATG5 Pathway in Gastric Cancer

2018 ◽  
Vol 46 (2) ◽  
pp. 847-859 ◽  
Author(s):  
Guoqing Pei ◽  
Meng Luo ◽  
Xiaochun Ni ◽  
Jugang Wu ◽  
Shoulian Wang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Drug Resistance ◽  
Molecular Mechanisms ◽  
Chemotherapy Resistance ◽  
Cell Counting ◽  
Cancer Resistance ◽  
Glycoprotein P ◽  
Real Time Quantitative Pcr ◽  
Mucosal Tissues ◽  
Underlying Mechanisms

Background/Aims: Metadherin (MTDH) is overexpressed in some malignancies and enhances drug resistance; however, its role in gastric cancer (GC) and the underlying mechanisms remain largely unexplored. Here, we explore the mechanism by which MTDH induces drug resistance in GC. Methods: We analysed the level of MTDH in GC and adjacent normal gastric mucosal tissues by real-time quantitative PCR (q-PCR). We also analysed the level of autophagy by western blot analysis, confocal microscopy, and transmission electron microscopy after MTDH knockdown and overexpression, and examined fluorouracil (5-FU) resistance by Cell Counting Kit-8 at the same time. Finally, GC patient-derived xenograft tumours were used to demonstrate 5-FU resistance. An AMPK pathway inhibitor was applied to determine the molecular mechanisms of autophagy. Results: MTDH expression was significantly increased in the GC specimens compared with that in the adjacent normal gastric mucosal tissues. Further study showed a positive correlation between the expression level of MTDH and 5-FU resistance. MTDH overexpression in MKN45 cells increased the levels of P-glycoprotein (P-gp) and promoted 5-FU resistance, while inhibition of MTDH showed the opposite result. The simultaneous inhibition of autophagy and overexpression of MTDH decreased the levels of P-gp and inhibited 5-FU resistance. Moreover, MTDH induced AMPK phosphorylation, regulated ATG5 expression, and finally influenced autophagy, suggesting that MTDH may activate autophagy via the AMPK/ATG5 signalling pathway. Our findings reveal a unique mechanism by which MTDH promotes GC chemoresistance and show that MTDH is a potential target for improved chemotherapeutic sensitivity and GC patient survival. Conclusions: MTDH-stimulated cancer resistance to 5-FU may be mediated through autophagy activated by the AMPK/ATG5 pathway in GC.

scholarly journals The Role of Autophagy in Gastric Cancer Chemoresistance: Friend or Foe?

2020 ◽  
Vol 8 ◽  
Author(s):  
Jing-Li Xu ◽  
Li Yuan ◽  
Yan-Cheng Tang ◽  
Zhi-Yuan Xu ◽  
Han-Dong Xu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Drug Resistance ◽  
Molecular Mechanisms ◽  
Chemotherapy Resistance ◽  
Dual Roles ◽  
Non Coding Rnas ◽  
Regulatory Effects ◽  
Cancer Chemoresistance ◽  
The Relationship

Gastric cancer is the third most common cause of cancer-related death worldwide. Drug resistance is the main inevitable and vital factor leading to a low 5-year survival rate for patients with gastric cancer. Autophagy, as a highly conserved homeostatic pathway, is mainly regulated by different proteins and non-coding RNAs (ncRNAs) and plays dual roles in drug resistance of gastric cancer. Thus, targeting key regulatory nodes in the process of autophagy by small molecule inhibitors or activators has become one of the most promising strategies for the treatment of gastric cancer in recent years. In this review, we provide a systematic summary focusing on the relationship between autophagy and chemotherapy resistance in gastric cancer. We comprehensively discuss the roles and molecular mechanisms of multiple proteins and the emerging ncRNAs including miRNAs and lncRNAs in the regulation of autophagy pathways and gastric cancer chemoresistance. We also summarize the regulatory effects of autophagy inhibitor and activators on gastric cancer chemoresistance. Understanding the vital roles of autophagy in gastric cancer chemoresistance will provide novel opportunities to develop promising therapeutic strategies for gastric cancer.

scholarly journals The anti-alcohol dependency drug disulfiram inhibits the viability and progression of gastric cancer cells by regulating the Wnt and NF-κB pathways

2020 ◽  
Vol 48 (6) ◽  
pp. 030006052092599 ◽  
Author(s):  
Jun Zhang ◽  
Ke Pu ◽  
Suyang Bai ◽  
Yukui Peng ◽  
Fan Li ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Cell Counting ◽  
Migration And Invasion ◽  
Gastric Cancer Cells ◽  
Gastric Cancer Cell Lines ◽  
Proliferation And Metastasis ◽  
Underlying Mechanisms ◽  
Related Proteins

Objective Disulfiram is commonly used for alcohol abuse; however, recent studies have revealed its potential as an anti-cancer treatment. This study investigated the effects of disulfiram on gastric cancer and its underlying mechanisms of action. Methods The gastric cancer cell lines MKN-45 and SGC-7901 were used for all experiments. Cell proliferation was investigated using cell counting kit-8, cell migration and invasion were examined using Transwell assays, the proliferation and metastasis related proteins PCNA and MMP-2, respectively, were detected by ELISA. To explore the underlying molecular mechanisms, we also examined levels of proteins involved in the Wnt and NF-κB pathways by ELISA. Results Disulfiram significantly inhibited the proliferation, migration, and invasion of gastric cancer cells and decreased PCNA and MMP-2 levels. Additionally, disulfiram-treated MKN-45 and SGC-7901 cells showed reduced expression of Wnt, β-catenin, and NF-κB. Conclusion Disulfiram regulates the Wnt and NF-κB pathways, and thus could be a potential treatment for managing gastric cancer.

Effects and Mechanisms of Anlotinib and Dihydroartemisinin Combination Therapy in Ameliorating Malignant Biological Behavior of Gastric Cancer Cells

2020 ◽  
Vol 21 ◽  
Author(s):  
Qiong Luo ◽  
Suyun Zhang ◽  
Donghuan Zhang ◽  
Rui Feng ◽  
Nan Li ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Chorioallantoic Membrane ◽  
Cell Counting ◽  
Biological Behavior ◽  
Gastric Cancer Cells ◽  
Invasion And Migration ◽  
Apoptosis Related Protein ◽  
And Migration

Background: Gastric cancer(GC) is currently one of the major malignancies that threatens human lives and health. Anlotinib is a novel small-molecule that inhibits angiogenesis to exert anti-tumor effects. However, the function in gastric cancer is incompletely understood. Objective: The aim of the present study was to investigate the anti-tumor effects and molecular mechanisms of anlotinib combined with dihydroartemisinin (DHA) in SGC7901 gastric cancer cells. Method: Different concentrations of anlotinib and DHA were used to treat SGC7901 gastric cancer cells, after which cell proliferation was measured. Drug interactions of anlotinib and DHA were analyzed by the Chou-Talalay method with CompuSyn software. proliferation, apoptosis, invasion, migration, and angiogenesis were measured using the cell counting kit-8 (CCK8) assay, flow cytometry, Transwell invasion assays, scratch assays, and chicken chorioallantoic membrane (CAM) assays. proliferation-associated protein (Ki67), apoptosis-related protein (Bcl-2), and vascular endothelial growth factor A (VEGF-A) were quantified by Western bloting. Results: The combination of 2.5 μmol/L of anlotinib and 5 of μmol/L DHA was highly synergistic in inhibiting cell growth, significantly increased the apoptosis rate and suppressed obviously the invasion and migration capability and angiogenesis of gastric cancer cells. In addition, the expression levels of Ki67, Bcl-2, and VEGF-A, as well as angiogenesis, were significantly decreased in the Combination of drugs compared with in control and either drug alone. Conclusion: The combination of anlotinib and DHA showed synergistic antitumor activity, suggesting their potential in treating patients with gastric cancer.

scholarly journals Mechanisms of Action And Clinical Implications of MicroRNAs in the Drug Resistance of Gastric Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Ying Liu ◽  
Xiang Ao ◽  
Guoqiang Ji ◽  
Yuan Zhang ◽  
Wanpeng Yu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Drug Resistance ◽  
Molecular Mechanisms ◽  
Malignant Tumors ◽  
Life Quality ◽  
Therapeutic Targets ◽  
Chemotherapeutic Agents ◽  
Response To Chemotherapy ◽  
Novel Biomarkers ◽  
Related Proteins

Gastric cancer (GC) is one of the most common malignant tumors of digestive systems worldwide, with high recurrence and mortality. Chemotherapy is still the standard treatment option for GC and can effectively improve the survival and life quality of GC patients. However, with the emergence of drug resistance, the clinical application of chemotherapeutic agents has been seriously restricted in GC patients. Although the mechanisms of drug resistance have been broadly investigated, they are still largely unknown. MicroRNAs (miRNAs) are a large group of small non-coding RNAs (ncRNAs) widely involved in the occurrence and progression of many cancer types, including GC. An increasing amount of evidence suggests that miRNAs may play crucial roles in the development of drug resistance by regulating some drug resistance-related proteins as well as gene expression. Some also exhibit great potential as novel biomarkers for predicting drug response to chemotherapy and therapeutic targets for GC patients. In this review, we systematically summarize recent advances in miRNAs and focus on their molecular mechanisms in the development of drug resistance in GC progression. We also highlight the potential of drug resistance-related miRNAs as biomarkers and therapeutic targets for GC patients.

Celastrol Inhibits the Proliferation and Decreases Drug Resistance of Cisplatin-Resistant Gastric Cancer SGC7901/DDP Cells

2021 ◽  
Vol 21 ◽  
Author(s):  
Dongmei Zhan ◽  
Tengyang Ni ◽  
Haibo Wang ◽  
Mengying Lv ◽  
Masataka Sunagawa ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Drug Resistance ◽  
Signaling Pathway ◽  
Resistance Index ◽  
Mtor Signaling ◽  
Control Group ◽  
Human Gastric Cancer ◽  
Cancer Resistance ◽  
Mtor Signaling Pathway ◽  
Expression Levels

Background: This study aimed to determine the effect and mechanism of Celastrol inhibiting the proliferation and decreases drug resistance of cisplatin-resistant gastric cancer cells. Objective: To explore the effect and mechanism of Celastrol on proliferation and drug resistance of human gastric cancer cisplatin-resistant cells SGC7901/DDP. Methods: The thiazole blue (MTT) method was used to detect the sensitivity of human gastric cancer cisplatin-resistant cells SGC7901/DPP to cisplatin and Celastrol to determine the Drug resistance index (DRI). According to the half inhibitory concentration (IC50) value, the action concentration of the following experimental drugs was set to reduce the cytotoxicity; Annexin V-FITC/PI double staining method was used to detect the apoptosis of SGC7901/DDP cells induced by Celastrol; Western Blot was used to examine the expression levels of P-glycoprotein (P-gp), Multidrug Resistance Associated Protein 1 (MRP1), Breast Cancer Resistance Associated Protein (Breast Cancer Resistance)-relative protein (BCRP), and mechanistic Target of Rapamycin (mTOR) pathway related proteins; Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) was used to detect the mRNA expression levels of P-gp, MRP1, and BCRP. Results: (1) Compared with the control group (We set the untreated group as the control group), the proliferation of the SGC7901/DPP cells was significantly inhibited after treating with 0.1-6.4μmol/L Celastrol in a time- and concentration-dependent manner (P<0.05). The Drug resistance index DRI of the SGC7901/DPP cells to DDP was 5.64. (2) Compared with the control group, Celastrol could significantly inhibit the proliferation and induce the apoptosis of the SGC7901/DPP cells (P<0.05). (3) The mRNA and protein expression levels of P-gp, MRP1, and BCRP in the SGC7901/DPP cells were significantly higher than those in the SGC7901 cells. However, after treating with Celastrol, the expression levels of P-gp, MRP1, and BCRP in the SGC7901/DPP cells were significantly reduced (P<0.05). (4) Compared with the control group, the Celastrol treatment also reduced the expression of the mTOR signaling pathway related proteins, suggesting that the mTOR signaling pathway may be involved in the process of Celastrol inhibiting the proliferation of the SGC7901/DDP cells and reducing their drug resistance. (5) Significantly, the combination of Celastrol and DDP reduced the expression of P-gp, MRP1, and BCRP in the SGC7901/DPP cells. Conclusion: Celastrol can inhibit the proliferation of the SGC7901/DDP cells, induce their apoptosis, and reduce the expression of drug resistance genes, probably by inhibiting the expression of the proteins related to the mTOR signaling pathway.

Current Advances and Outlook in Gastric Cancer Chemoresistance: A Review

2021 ◽  
Vol 16 ◽  
Author(s):  
Sheng-Xiong Zhang ◽  
Wei Liu ◽  
Bo Ai ◽  
Ling-Ling Sun ◽  
Zhe-Sheng Chen ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Drug Resistance ◽  
Natural Products ◽  
Chemotherapy Resistance ◽  
Underlying Mechanism ◽  
Primary Treatment ◽  
New Drugs ◽  
Cancer Drug ◽  
Cancer Drug Resistance ◽  
Cancer Pharmacology

Background: Surgical resection of the lesion is the standard primary treatment of gastric cancer. Unfortunately, most patients are already in the advanced stage of the disease when they are diagnosed with gastric cancer. Alternative therapies, such as radiation therapy and chemotherapy, can achieve only very limited benefits. The emergence of cancer drug resistance has always been the major obstacle to the cure of tumors. The main goal of modern cancer pharmacology is to determine the underlying mechanism of anticancer drugs. Objective: Here, we mainly review the latest research results related to the mechanism of chemotherapy resistance in gastric cancer, the application of natural products in overcoming the chemotherapy resistance of gastric cancer, and the new strategies currently being developed to treat tumors based on immunotherapy and gene therapy. Conclusion: The emergence of cancer drug resistance is the main obstacle in achieving alleviation and final cure for gastric cancer. Mixed therapies are considered to be a possible way to overcome chemoresistance. Natural products are the main resource for discovering new drugs specific for treating chemoresistance, and further research is needed to clarify the mechanism of natural product activity in patients. 

Rab27B enhances drug resistance in hepatocellular carcinoma by promoting exosome-mediated drug efflux

2020 ◽  
Vol 41 (11) ◽  
pp. 1583-1591 ◽  
Author(s):  
Rui Li ◽  
Chengyong Dong ◽  
Keqiu Jiang ◽  
Rui Sun ◽  
Yang Zhou ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Liver Cancer ◽  
Therapeutic Effect ◽  
Efflux Pump ◽  
Human Life ◽  
Therapeutic Effects ◽  
Drug Efflux ◽  
Glycoprotein P ◽  
Chemotherapy Drugs ◽  
Underlying Mechanisms

Abstract Liver cancer is a major threat to human life and health, and chemotherapy has been the standard non-surgical treatment for liver cancer. However, the emergence of drug resistance of liver cancer cells has hindered the therapeutic effect of chemical drugs. The discovery of exosomes has provided new insights into the mechanisms underlying tumour cell resistance. In this study, we aimed to determine the proteins associated with drug resistance in tumour cells and to elucidate the underlying mechanisms. We found that Rab27B expression in drug (5-fluorouracil, 5Fu)-resistant Bel7402 (Bel/5Fu) cells increased significantly compared with that in drug-sensitive Bel7402 cells. In addition, Bel/5Fu cells secreted more exosomes under 5Fu stimulation. The number of exosomes secreted by Bel/5Fu cells significantly reduced after knocking down Rab27B, and the cellular concentration of 5Fu increased, enhancing its therapeutic effect. We also found that the administration of classical drug efflux pump (P-glycoprotein, P-gp) inhibitors together with knockdown of Rab27B further improved the therapeutic effects of chemotherapy drugs. In conclusion, our findings suggest that Rab27B could be a new therapeutic target in liver cancer.

scholarly journals LncRNA FEZF1-AS1 Promotes Multi-Drug Resistance of Gastric Cancer Cells via Upregulating ATG5

2021 ◽  
Vol 9 ◽  
Author(s):  
Zhifu Gui ◽  
Zhenguo Zhao ◽  
Qi Sun ◽  
Guoyi Shao ◽  
Jianming Huang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Drug Resistance ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Underlying Mechanism ◽  
Multi Drug Resistance ◽  
Gastric Cancer Cells ◽  
Poor Overall Survival

Long non-coding RNAs (lncRNAs) play important roles in human cancers including gastric cancer (GC). Dysregulation of lncRNAs is involved in a variety of pathological activities associated with gastric cancer progression and chemo-resistance. However, the role and molecular mechanisms of FEZF1-AS1 in chemoresistance of GC remain unknown. In this study, we aimed to determine the role of FEZF1-AS1 in chemoresistance of GC. The level of FEZF1-AS1 in GC tissues and GC cell lines was assessed by qRT-PCR. Our results showed that the expression of FEZF1-AS1 was higher in gastric cancer tissues than in adjacent normal tissues. Multivariate analysis identified that high level of FEZF1-AS1 is an independent predictor for poor overall survival. Increased FEZF1-AS1 expression promoted gastric cancer cell proliferation in vitro. Additionally, FEZF1-AS1 was upregulated in chemo-resistant GC tissues. The regulatory effect of FEZF1-AS1 on multi-drug resistance (MDR) in GC cells and the underlying mechanism was investigated. It was found that increased FEZF1-AS1 expression promoted chemo-resistance of GC cells. Molecular interactions were determined by RNA immunoprecipitation (RIP) and the results showed that FEZF1-AS1 regulated chemo-resistance of GC cells through modulating autophagy by directly targeting ATG5. The proliferation and autophagy of GC cells promoted by overexpression of LncFEZF1-AS1 was suppressed when ATG5 was knocked down. Moreover, knockdown of FEZF1-AS1 inhibited tumor growth and increased 5-FU sensitivity in GC cells in vivo. Taken together, this study revealed that the FEZF1-AS1/ATG5 axis regulates MDR of GC cells via modulating autophagy.

scholarly journals Hepatitis C Virus-Induced FUT8 Causes 5-FU Drug Resistance in Human Hepatoma Huh7.5.1 Cells

Viruses ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 378 ◽  
Author(s):  
Shu Li ◽  
Xiao-Yu Liu ◽  
Qiu Pan ◽  
Jian Wu ◽  
Zhi-Hao Liu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Chemotherapy Resistance ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Release Assay ◽  
Polymerase Chain ◽  
Multidrug Resistance Related Protein

Hepatitis C virus (HCV) is a major cause of human chronic liver disease and hepatocellular carcinoma. Our recent studies showed that α1,6-fucosyltransferase (FUT8), a key glycosyltransferase, was the most up-regulated glycosyltransferase after the HCV infection of human hepatocellular carcinoma Huh7.5.1 cells. Here, we further studied the effects and possible mechanism of FUT8 on the proliferation of HCV and chemotherapy-resistance of HCV-infected Huh7.5.1 cells. The effects of FUT8 on the proliferation and drug resistance of HCV-infected Huh7.5.1 cells were analyzed by flow cytometry analysis (FCM), quantitative real-time polymerase chain reaction (qRT-PCR), Western blot analysis and lactate dehydrogenase (LDH) release assay. Results: We found that FUT8 not only promoted Huh7.5.1 proliferation by activating PI3K-AKT-NF-κB signaling, but also stimulated the expression of the drug-resistant proteins P-glycoprotein (P-gp) and multidrug resistance related protein 1 (MRP1) and enhanced the 5-fluorouracil (5-FU) chemo-resistance of Huh7.5.1 cells. Silencing of FUT8 reduced the cell proliferation and increased the 5-FU sensitivity of HCV-infected Huh7.5.1 cells. Inhibition of P-gp and MRP1 increased the 5-FU drug sensitivity in HCV infected Huh7.5.1 cells. HCV-induced FUT8 promotes proliferation and 5-FU resistance of Huh7.5.1 cells. FUT8 may serve as a therapeutic target to reverse chemotherapy resistance in HCV-infected Huh7.5.1 cells.

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