Jaridon 6, a new diterpene from Rabdosia rubescens (Hemsl.) Hara, can display anti‐gastric cancer resistance by inhibiting SIRT1 and inducing autophagy

2021 ◽  
Author(s):  
Ling Fu ◽  
Bing‐Kai Han ◽  
Fang‐Feng Meng ◽  
Jun‐Wei Wang ◽  
Tian‐Ye Wang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Resistance ◽  
Rabdosia Rubescens

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.

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 Effects and Mechanism of Dihydroartemisinin on Malignant Behavior of Cisplatin-Resistant Gastric Cancer Cells

2018 ◽  
Vol 4 (Supplement 2) ◽  
pp. 215s-215s
Author(s):  
S. Zhang ◽  
R. Feng ◽  
F. Yuan ◽  
X. Chen ◽  
N. Li ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Cisplatin Resistance ◽  
Expression Level ◽  
Dependent Manner ◽  
Cancer Resistance ◽  
Gastric Cancer Cells ◽  
Concentration Dependent Manner ◽  
Expression Levels ◽  
Malignant Behavior

Background: Studies showed that dihydroartemisinin (DHA) has significant antitumor effects. However, there have been no relevant reports on gastric cancer resistance to DHA. Aim: To investigate the influence of DHA on the malignant behavior of cisplatin (DDP)-resistant gastric cancer cells SGC7901/DDP and the possible molecular mechanism. Methods: The IC50 of DHA against SGC7901/DDP cells at 48 h was obtained with CCK-8. DHA was used against SGC7901/DDP, with IC50 concentration at 0 µmol/L, 0.5-fold, onefold, and twofold respectively. Then the proliferation activity of SGC7901/DDP from day 1 to day 5 was detected by CCK-8. At 48 h after DHA treatment, we observed apoptosis, invasion, and migration, evaluated autophagy, and detected the expression level of protein related to the regulation of autophagy, apoptosis, angiogenesis and lymphangiogenesis with Western blot. The influence of DHA on cisplatin resistance of SGC7901/DDP was detected through sensitization test and the evaluation of p-gp expression level. Results: The IC50 concentration of DHA against SGC7901/DDP cells at 48 h is 70 µmol/L. DHA significantly inhibited the proliferation of SGC7901/DDP, which was time- and concentration-dependent (all P < 0.05). After having been treated for 48 h by increasing concentrations of DHA (0, 35, 70 and 140 µmol/L), the apoptosis rate increased and the penetrating cell number and scratch healing rate significantly decreased (all P < 0.05). The expression levels of Beclin1 and LC3-II/LC3-I which were corrected with autophagy, and the formation of autophagosomes and autophagous vacuoles increased in a concentration-dependent manner (all P < 0.05). The total PI3K, Akt, and mTOR expression levels did not significantly change, but their phosphorylated products (PI3P, p-Akt [Ser473], and p-mTOR) showed concentration-dependent decreases (all P < 0.05). The expression of caspases-8/9/3 protein significantly increased while the expression of VEGF-A、VEGF-C protein decreased (all P < 0.05). DHA could reverse the resistance of SGC7901/DDP cells to cisplatin after DHA treatment at a nontoxic dose (15.23 µg/mL) with a reversal rate of 2.95. After DHA treatment at different concentrations for 48 h, the expression of p-gp was significantly reduced in a concentration-dependent manner ( P < 0.05). Conclusion: DHA significantly inhibited proliferation, promoted programmed death, and had anti-invasion and antimetastatic effects on SGC7901/DDP cells, probably by upregulating autophagy-related Beclin1 and LC3-II expression and by inhibiting the antiautophagy signaling pathway PI3K/AKT/mTOR, thus promoting autophagic death. In addition, DHA induced caspase-dependent and mitochondrial pathway apoptosis in SGC7901/DDP cells, and reduced VEGF-A and VEGF-C activity to promote antiangiogenesis and antilymphangiogenesis. Furthermore, DHA effectively reversed the cisplatin resistance of gastric cancer cell by inhibiting p-gp expression.

Use of DARPP-32 to increase interactions between EGFR and ERBB3 and to promote gastric cancer resistance to gefitinib.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 18-18 ◽  
Author(s):  
Shoumin Zhu ◽  
Abbes Belkhiri ◽  
Alexander Zaika ◽  
Wael El-Rifai
Keyword(s):  
Gastric Cancer ◽  
Molecular Mechanisms ◽  
Annexin V ◽  
Predictive Biomarker ◽  
Clonogenic Survival ◽  
Cancer Prognosis ◽  
Response To Treatment ◽  
Akt Pathway ◽  
Cancer Resistance ◽  
Gastric Cancer Cells

18 Background: Dopamine and cAMP-regulated phosphoprotein, Mr 32000 (DARPP−32), is overexpressed during gastric carcinogenesis. Gefitinib is a specific and effective EGFR inhibitor that has shown antitumor activity in clinical trials against gastrointestinal cancers. Gastric tumors can become resistant to gefitinib. However, molecular mechanisms that mediate resistance to gefitinib remain poorly understood. Methods: The expression of DARPP−32 in the multi-step carcinogenesis cascade was examined using IHC analysis. Cell survival was determined by clonogenic survival and ATP−Glo assays. Apoptosis was assessed by Annexin-V and immunoblot analyses. The association between DARPP−32 and EGFR was evaluated by immunofluorescence and co-IP assays. Results: The composite expression score progressively increased significantly from normal or gastritis to adenocarcinoma (p<0.001). Overexpression of DARPP−32 in MKN-28 cells blocked gefitinib-induced apoptosis and increased the drug’s IC50 10−fold, compared to that of control cells (P<0.01). And DARPP-32 expressing MKN−28 cells had activated the PI3K-AKT pathway as compared to control cells. The three−way co-IP experiments demonstrated the existence of DARPP-32, EGFR, and ERBB3 in the same protein complex. DARPP-32 enhanced EGFR-ERBB3 heterodimerization promoting phosphorylation of ERBB3, and then activated the PI3K-AKT pathway. Following treatment with gefitinib (25 μM) overnight, MKN−28 cells expressing DARPP-32 displayed stable protein levels of EGFR. The knockdown of endogenous DARPP-32 by DARPP-32 shRNA in SNU-16 cell lines reversed these signaling effects and increased sensitivity to gefitinib (p<0.01). Conclusions: Our results suggest that DARPP-32 overexpression may participate in the progression to neoplasia. DARPP-32 also plays a role in increasing the stability of EGFR protein; DARPP-32 promotes resistance of gastric cancer cells to gefitinib by promoting interaction between EGFR and ERBB3 and activating PI3K–AKT signaling. DARPP-32 may have potential as a predictive biomarker in gastric cancer prognosis and clinical response to treatment.

Gene’s co-expression network and experimental validation of molecular markers associated with the drug resistance of gastric cancer

2020 ◽  
Vol 14 (9) ◽  
pp. 761-773
Author(s):  
Wenqian Qi ◽  
Qian Zhang
Keyword(s):  
Gastric Cancer ◽  
Drug Resistance ◽  
Molecular Markers ◽  
Human Gastric Cancer ◽  
Cancer Resistance ◽  
Gastric Cancer Cells ◽  
Network Analyses ◽  
Potential Factors ◽  
Function Enrichment

Aim: Chemotherapy can significantly improve the overall survival rate of patients with gastric cancer; however, so far little is known about the molecular mechanism of resistance to chemotherapy. Therefore, this study was proposed to elucidate molecular markers of resistance to chemotherapeutic agent in gastric cancer. Materials & methods: Weighted gene co-expression network analyses were performed in gastric cancer cohort. The most relevant genes modules for gastric cancer resistance were selected. Gene oncology function enrichment of genes was conducted. The biological function of resistant genes were identified in vitro. Results & conclusion: Two resistant hub genes, SPTBN1 and LAMP1, were selected. Experiments showed that downregulation of SPTBN1and LAMP1 proteins significantly enhanced the sensitivity of human gastric cancer cells SGC7901 to 5-FU and cisplatin. Thus, our results provide a baseline about the potential factors of drug resistance in gastric cancer.

scholarly journals PO-501 Deconstructing the role of CD44 in gastric cancer resistance to cisplatin

2018 ◽  
Author(s):  
C Pereira ◽  
D Ferreira ◽  
P Granja ◽  
G Almeida ◽  
C Oliveira
Keyword(s):  
Gastric Cancer ◽  
Cancer Resistance

Ultrastructural Cytochemical Study of Human Gastric Cancer: Observation of AKP ase,ACP ase,G6P ase,TPP ase and CO ase

1990 ◽  
Vol 48 (3) ◽  
pp. 254-255
Author(s):  
Dong Yuming ◽  
Yang Guanglin ◽  
Du Wei Dong ◽  
Xu Ai Liam
Keyword(s):  
Gastric Cancer ◽  
Gastric Epithelium ◽  
Human Gastric Cancer ◽  
Electron Microscopic ◽  
Cytochemical Study ◽  
Electron Microscopic Cytochemistry ◽  
Cytochemical Reaction ◽  
Set Up ◽  
Cancer Tissues ◽  
Cytochemical Technique

The activities and distributions of AKPase ,ACPase,G6Pase,TPPase and COase in human normal gastric mucosa and gastric cancer tissues were studied histochemically at light microscopic level. These enzymes are the marker enzymes of cell membrane lysosome endoplasmic reticulum, Golgi apparatus and mitochondrion objectively. On the basis of the research we set up a special ultrastructural cytochemical technique and first researched into gastric cancer domesticly. Ultrastructural cytochemistry is also called electron microscopic cytochemistry. This new technique possesses both the sensitivity of cytochemical reaction andi the high resolution of electron microscope. It is characterized by direct observation,exact localization and the combination morphology with function.The distributions of AKPase,ACPase,G6Pase,TPPase and COase in 14 cases of gastric cancer and 1 case of gastric Denign lesion were studied ultrastructurally. The results showed: 1. normal gastric epithelium had no AKPase reaction. The reaction of ACPase,G6Pase,TPPase and Coase were found in the corresponding organella, which were consistent with their function.

Ultrastructural Localization Study of Carcinoembryonic Antigen (CEA) in Gastric Cancer: Immunoelectron Microscopic Observation

1990 ◽  
Vol 48 (3) ◽  
pp. 252-253
Author(s):  
Dong Yuming ◽  
Yang Guanglin ◽  
Wu Jifeng ◽  
Chen Xiaolin
Keyword(s):  
Gastric Cancer ◽  
Intestinal Metaplasia ◽  
Cancer Cells ◽  
Microscopic Observation ◽  
Biological Significance ◽  
Ultrastructural Localization ◽  
Mucinous Carcinoma ◽  
Surface Glycoprotein ◽  
Tubular Adenocarcinoma ◽  
Pap Method

On the basis of light microscopic observation, the ultrastructural localization of CEA in gastric cancer was studied by immunoelectron microscopic technique. The distribution of CEA in gastric cancer and its biological significance and the mechanism of abnormal distribution of CEA were further discussed.Among 104 surgically resected specimens of gastric cancer with PAP method at light microscopic level, the incidence of CEA(+) was 85.58%. All of mucinous carcinoma exhibited CEA(+). In tubular adenocarcinoma the incidence of CEA(+) showed a tendency to rising with the increase of degree of differentiation. In normal epithelia and intestinal metaplasia CEA was faintly present and was found only in the luminal surface. The CEA staining patterns in cancer cells were of three types--- cytoplasmic, membranous and weak reactive type. The ultrastructural localization of CEA in 14 cases of gastric cancer was studied by immunoelectron microscopic technique.There was a little or no CEA in the microvilli of normal epithelia. In intestinal metaplasia CEA was found on the microvilli of absorptive cells and among the mucus particles of goblet cells. In gastric cancer CEA was also distributed on the lateral and basal surface or even over the entire surface of cancer cells and lost their polarity completely. Many studies had proved that the alterations in surface glycoprotein were characteristic changes of tumor cells. The antigenic determinant of CEA was glycoprotein, so the alterations of tumor-associated surface glycoprotein opened up a new way for the diagnosis of tumors.

Reduced expression of TMEM166 is associated with esophageal carcinoma and gastric cancer

2010 ◽  
Vol 34 (8) ◽  
pp. S54-S54
Author(s):  
Dong Xu ◽  
Ying Chang ◽  
Huiying He ◽  
Yingyu Chen
Keyword(s):  
Gastric Cancer ◽  
Esophageal Carcinoma
Sign in / Sign up

Export Citation Format

Share Document