scholarly journals METTL3-Mediated DLGAP1 Antisense RNA 2 Promotes Gastric Cancer Tumorigenesis Through Facilitating C-Myc-Dependent Warburg Effect

2021 ◽  
Author(s):  
Changshun Yang ◽  
Yu Zhang ◽  
Xuefei Cheng ◽  
Weihua Li
Keyword(s):  
Gastric Cancer ◽  
Antisense Rna ◽  
Warburg Effect ◽  
Aerobic Glycolysis ◽  
Dependent Manner ◽  
Rna Immunoprecipitation ◽  
The Stability ◽  
A Site ◽  
Rip Assay ◽  
Site Binding

Abstract Background The critical roles of N6-methyladenosine (m6A) modification have been demonstrated by more and more evidence. However, the cross-talking of m6A and long non-coding RNAs (lncRNAs) in gastric cancer (GC) tumorigenesis is still unclear. Here, our work focused on the functions and molecular mechanism of m6A-modified lncRNA DLGAP1 antisense RNA 2 (DLGAP1-AS2) in GC. Methods LncRNA expression profile data was derived from GEO. M6A profile was screened using Methylated RNA immunoprecipitation sequencing (MeRIP-Seq). The metabolism assays were conducted using quantitative analysis of glucose, lactate, ATP and extracellular acidification rate (ECAR). The m6A level of specific RNA was identified using MeRIP-qPCR. The molecular interaction was detected using RIP assay. Results Microarray analysis found that lncRNA DLGAP1-AS2 up-regulated in GC cells. Clinical data showed that DLGAP1-AS2 high-expression was correlated with advanced pathological stage and poor prognosis. Functionally, DLGAP1-AS2 promoted the Warburg effect (aerobic glycolysis) and knockdown of DLGAP1-AS2 suppressed the tumor growth of GC cells. Mechanistically, m6A methyltransferase METTL3 enhanced the stability of DLGAP1-AS2 via m6A site binding. Moreover, DLGAP1-AS2 interacted with YTHDF1 to enhance the stability of c-Myc mRNA through DLGAP1-AS2/m6A/YTHDF1/c-Myc mRNA. Conclusions In conclusion, our work indicates the functions of m6A-modified DLGAP1-AS2 in the GC aerobic glycolysis, disclosing a potential m6A-dependent manner for GC treatment.

scholarly journals N6-methyladenosine Reader YTHDF1-induced lncRNA DLGAP1-AS2 Promotes the c-Myc Mediated Gastric Cancer Aerobic Glycolysis

2021 ◽  
Author(s):  
Changshun Yang ◽  
Yu Zhang ◽  
Xuefei Cheng ◽  
Weihua Li
Keyword(s):  
Gastric Cancer ◽  
Aerobic Glycolysis ◽  
Profile Data ◽  
Extracellular Acidification ◽  
Rna Immunoprecipitation ◽  
Non Coding Rnas ◽  
Essential Function ◽  
The Stability ◽  
Rip Assay ◽  
Advanced Pathological Stage

Abstract Background: Emerging data has demonstrated the essential function of N6-methyladenosine (m6A) modification of long non-coding RNAs (lncRNAs) in human tumorigenesis. Nevertheless, the regulation of m6A-lncRNA approach on gastric cancer (GC) tumorigenesis is unclear. Methods: LncRNA expression profile data was derived from GEO. M6A profile was screened using Methylated RNA immunoprecipitation sequencing (MeRIP-Seq). The metabolism assays were conducted using quantitative analysis of glucose, lactate, ATP and extracellular acidification rate (ECAR). The m6A level of specific RNA was identified using MeRIP-qPCR. The molecular interaction was detected using RIP assay.Results: In the findings, results showed that enhanced DLGAP1-AS2 expression was correlated with advanced pathological stage and poor prognosis. Functionally, DLGAP1-AS2 promoted the aerobic glycolysis and knockdown of DLGAP1-AS2 suppressed the tumor growth of GC cells. Mechanistically, m6A reader YTHDF1 accelerated the enrichment of DLGAP1-AS2 in GC. Moreover, DLGAP1-AS2 interacted with YTHDF1 to integrate c-Myc mRNA, thereby enhancing the stability of c-Myc mRNA through DLGAP1-AS2/m6A/YTHDF1/c-Myc mRNA. Conclusions: In conclusion, our work indicates a novel m6A-maintained lncRNA DLGAP1-AS2 in the GC aerobic glycolysis, disclosing a m6A-reader-dependent modality regulation.

scholarly journals PKM2 Is the Target of a Multi-Herb-Combined Decoction During the Inhibition of Gastric Cancer Progression

2021 ◽  
Vol 11 ◽  
Author(s):  
Qingmin Sun ◽  
Mengyun Yuan ◽  
Hongxing Wang ◽  
Xingxing Zhang ◽  
Ruijuan Zhang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Nuclear Translocation ◽  
Aerobic Glycolysis ◽  
Metabolic Reprogramming ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Gastric Cancer Cells ◽  
Mesenchymal Transition

Gastric cancer is the third leading cause of cancer death worldwide. Traditional Chinese medicine (TCM) is increasingly extensively applied as a complementary therapy for gastric cancer (GC) in China, which shows unique advantages in preventing gastric cancer metastasis. Previous study indicates modified Jian-pi-yang-zheng (mJPYZ) decoction inhibit the progression of gastric cancer by regulating tumor-associated macrophages (TAM). However, it is unclear whether mJPYZ can affect metabolic reprogramming of gastric cancer cells. Here, we showed that mJPYZ effectively attenuated GC cells proliferation, migration and invasion. Meantime, mJPYZ reduced the aerobic glycolysis level of GC cells in vivo and in vitro by regulating the expression and nuclear translocation of PKM2. Overexpression of PKM2 that could reverse the inhibitory effect of mJPYZ, migration and epithelial to mesenchymal transition (EMT). Our results showed PKM2/HIF-1α signaling was the key metabolic regulator of mJPYZ in GC cells. In summary, our present study suggested that abnormal PKM2 is required for maintaining the malignant phenotype of GC cells. The TCM decoction mJPYZ inhibited GC cells growth and EMT by reducing of glycolysis in PKM2 dependent manner. This evidence expanded our understanding of the anti-tumor mechanism of mJPYZ and further indicated mJPYZ a potential anti-tumor agent for GC patients.Chemical Compounds Studied in this ArticleRutin (PubChem CID: 5280805); Lobetyolin (PubChem CID: 53486204); Calycosin-7-glucoside (PubChem CID: 71571502); Formononetin (PubChem CID: 5280378); Calycosin (PubChem CID: 5280448); Ononin (PubChem CID: 442813); P-Coumaric Acid (PubChem CID: 637542).

scholarly journals Disulfiram Chelated With Copper Inhibits the Growth of Gastric Cancer Cells by Modulating Stress Response and Wnt/β-catenin Signaling

2020 ◽  
Vol 10 ◽  
Author(s):  
Ling Wang ◽  
Xiaoke Chai ◽  
Run Wan ◽  
Hong Zhang ◽  
Cong Zhou ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Stress Response ◽  
Aerobic Glycolysis ◽  
Autophagic Flux ◽  
Dependent Manner ◽  
Gastric Cancer Cells ◽  
Cu Complex ◽  
Induced Apoptosis

Disulfiram (DSF) is a well-known drug for alcohol abuse. In recent decades, DSF has been demonstrated to exhibit anti-tumor activity; DSF chelated with copper shows enhanced anti-tumor effect. Our goal was to explore the effect of DSF/Cu complex on the growth and metastasis of gastric cancer (GC) in vitro and in vivo. DSF/Cu complex suppressed the proliferation, migration of MKN-45 and BGC-823 GC cells. Furthermore, DSF/Cu treatment reduced the tumor volume in GC mouse models with a tumor suppression rate of 48.24%. Additionally, DSF/Cu induced apoptosis in vitro in MKN-45 and BGC-823 GC cells in a dose- and time-dependent manner as well as in vivo in the xenograft tumor mouse model. Furthermore, DSF/Cu induced autophagy and autophagic flux in MKN-45 and BGC-823 cells, increased the expression of autophagy-related Beclin-1 and LC3 proteins in vivo. Additionally, DSF/Cu suppressed aerobic glycolysis and oxidative phosphorylation by reducing oxygen consumption rate and extracellular acidification rate, respectively, in MKN-45 and BGC-823 cells. Treatment with DSF/Cu induced oxidative stress and DNA damage response by elevating the reactive oxygen species levels; increasing the expression of P53, P21, and γ-H2AX proteins; and inhibiting Wnt/β-catenin signaling in vitro and in vivo. Thus, DSF/Cu suppressed the growth and metastasis of GC cells via modulating the stress response and Wnt/β-catenin signaling. Hence, DSF may be used as a potential therapeutic agent for the treatment of GC.

scholarly journals H19 contributes to aerobic glycolysis, proliferation and immune escape of gastric cancer cells via the miR-519d-3p/LDHA axis

2020 ◽  
Author(s):  
Linqing Sun ◽  
Juntao Li ◽  
Wenying Yan ◽  
Zhendong Yao ◽  
Ruoqin Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gastric Cancer ◽  
Immune Escape ◽  
Aerobic Glycolysis ◽  
Quantitative Polymerase Chain Reaction ◽  
Lactate Production ◽  
Glucose Consumption ◽  
Luciferase Reporter ◽  
Dependent Manner ◽  
Γδt Cells

Abstract Background Long non-coding RNAs (lncRNAs) have been investigated in multiple human cancers including gastric cancer (GC). Our research aims to explore the role of H19 in aerobic glycolysis, proliferation, and immune escape of GC cells.Methods The expression of H19 in GC samples were analyzed using Gene Expression Profiling Interactive Analysis (GEPIA), Gene Expression Omnibus (GEO) data, and real-time quantitative polymerase chain reaction (RT-qPCR) analysis. Glucose consumption and lactate production were applied to assess the aerobic glycolysis of GC cells. Subcellular fractionation, luciferase reporter, and western blot assays certified the binding between genes. CCK-8 and colony formation assays were used to determine GC cell proliferation. Flow cytometry, ELISA, and RT-qPCR assays were applied to analyze the immunosuppressive effect of H19. Results H19 was highly expressed in samples of patients with GC, and associated with tumor growth in vivo. H19 knockdown suppressed glucose consumption, lactate production, proliferation of GC cells by regulating miR-519d-3p/LDHA axis. Both miR-519d-3p depletion and LDHA overexpression could reverse the H19 knockdown-induced decrease in aerobic glycolysis and proliferation. Moreover, conditioned medium (CM) from stable knockdown H19 GC cells modulated the activity of immune cells including γδT cells, Jurkat cells, and tumor-associated macrophages (TAMs) in a lactate dependent manner.Conclusions The H19/miR-519d-3p/LDHA axis mainly contributed to aerobic glycolysis, proliferation, and immune escape of GC cells.

scholarly journals Monomeric YoeB toxin retains RNase activity but adopts an obligate dimeric form for thermal stability

2019 ◽  
Vol 47 (19) ◽  
pp. 10400-10413 ◽  
Author(s):  
Ian J Pavelich ◽  
Tatsuya Maehigashi ◽  
Eric D Hoffer ◽  
Ajchareeya Ruangprasert ◽  
Stacey J Miles ◽  
...  
Keyword(s):  
Large Subunit ◽  
Dependent Manner ◽  
Type Ii ◽  
Substrate Selection ◽  
E Coli ◽  
Dimeric Form ◽  
The Stability ◽  
Stress Dependent ◽  
A Site ◽  
Sense Codon

Abstract Chromosomally-encoded toxin-antitoxin complexes are ubiquitous in bacteria and regulate growth through the release of the toxin component typically in a stress-dependent manner. Type II ribosome-dependent toxins adopt a RelE-family RNase fold and inhibit translation by degrading mRNAs while bound to the ribosome. Here, we present biochemical and structural studies of the Escherichia coli YoeB toxin interacting with both a UAA stop and an AAU sense codon in pre- and post-mRNA cleavage states to provide insights into possible mRNA substrate selection. Both mRNAs undergo minimal changes during the cleavage event in contrast to type II ribosome-dependent RelE toxin. Further, the 16S rRNA decoding site nucleotides that monitor the mRNA in the aminoacyl(A) site adopt different orientations depending upon which toxin is present. Although YoeB is a RelE family member, it is the sole ribosome-dependent toxin that is dimeric. We show that engineered monomeric YoeB is active against mRNAs bound to both the small and large subunit. However, the stability of monomeric YoeB is reduced ∼20°C, consistent with potential YoeB activation during heat shock in E. coli as previously demonstrated. These data provide a molecular basis for the ability of YoeB to function in response to thermal stress.

scholarly journals circATP2B1 Promotes Aerobic Glycolysis in Gastric Cancer Cells Through Regulation of the miR-326 Gene Cluster

2021 ◽  
Vol 11 ◽  
Author(s):  
Xihe Zhao ◽  
Zhong Tian ◽  
Lei Liu
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Gene Cluster ◽  
Noncoding Rna ◽  
Aerobic Glycolysis ◽  
Circular Rna ◽  
Metabolic Reprogramming ◽  
Luciferase Reporter ◽  
Dependent Manner ◽  
Gastric Cancer Cells

The discovery of circular RNA (circRNA) enormously complimented the repertoire of traditional gene expression theory. As a type of endogenous noncoding RNA, circRNA participates in the occurrence of many kinds of tumors in addition to regulating their development. The Warburg effect (aerobic glycolysis is taken with priority for cancer cells instead of oxidative phosphorylation) is one of the most important factors involved in the excessive proliferation of gastric cancer cells. Our data showed that circRNA circATP2B1 (also called hsa_circ_000826) was overexpressed in gastric cancer tissues instead of linear ATP2B1 mRNA, and it promoted aerobic glycolysis in gastric cancer cells. Bioinformatic Gene Ontology analysis showed that the potential downstream targets of circATP2B1 include the microRNA miR-326 gene cluster (miR-326-3p/miR-330-5p), which is functionally focused on cell growth and metabolic processes. The expressions of miR-326-3p/miR-330-5p were downregulated in gastric cancer, and circATP2B1 functionally targeted miR-326-3p/miR-330-5p in an RNA-induced silencing complex (RISC) dependent manner. Dual-luciferase reporter assays demonstrated that pyruvate kinase M2 (PKM2) was one of the targets of miR-326-3p/miR-330-5p. As a rate-limiting enzyme in the aerobic glycolytic pathway, PKM2 accelerated gastric cancer cells’ glucose uptake and increased cell viability. Taken together, circATP2B1 captured miR-326-3p/miR-330-5p and decreased the suppression of PKM2 by miR-326-3p/miR-330-5p, thus aiding the aerobic glycolysis and proliferation of gastric cancer cells. This study identified a novel molecular pathway in gastric cancer that may provide more targets for reversing cancer metabolic reprogramming, as well as a potential strategy for targeted therapy of gastric cancer.

scholarly journals Long Noncoding RNA PCED1B-AS1 Promotes the Warburg Effect and Tumorigenesis by Upregulating HIF-1α in Glioblastoma

2020 ◽  
Vol 29 ◽  
pp. 096368972090677 ◽  
Author(s):  
Zhiqiang Yao ◽  
Qiansheng Zhang ◽  
Fuyou Guo ◽  
Shewei Guo ◽  
Bo Yang ◽  
...  
Keyword(s):  
Long Noncoding Rna ◽  
Antisense Rna ◽  
Warburg Effect ◽  
Cancer Biology ◽  
Noncoding Rna ◽  
Prognostic Biomarker ◽  
Dependent Manner ◽  
The Warburg Effect

Accumulating evidence suggests that long noncoding RNA (lncRNA) functions as a critical regulator in cancer biology. Here, we characterized the role of lncRNA PCED1B antisense RNA 1 (PCED1B-AS1) in glioblastoma (GBM). PCED1B-AS1 was notably upregulated in GBM tissues and cell lines and closely associated with larger tumor size and higher grade. Patients with high PCED1B-AS1 had shorter survival time than those with low PCED1B-AS1. Functional experiments showed that depletion of PCED1B-AS1 significantly inhibited, while overexpression of PCED1B-AS1 promoted cell proliferation, glucose uptake, and lactate release. Mechanistically, PCED1B-AS1 was able to directly bind to the 5′-UTR of HIF-1α mRNA and potentiate HIF-1α translation, leading to increased HIF-1α protein level, thereby promoting the Warburg effect and tumorigenesis. Importantly, PCED1B-AS1 lost the carcinogenic properties in the absence of HIF-1α. In addition, we also confirmed the existence of the PCED1B-AS1/HIF-1α regulatory axis in vivo. Taken together, our findings demonstrate that PCED1B-AS1 is a novel oncogenic lncRNA in GBM and functions in a HIF-1α-dependent manner, which provides a promising prognostic biomarker and druggable target for GBM.

scholarly journals LINC00242/miR-1-3p/G6PD axis regulates Warburg effect and affects gastric cancer proliferation and apoptosis

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Peng Deng ◽  
Kai Li ◽  
Feng Gu ◽  
Tao Zhang ◽  
Wenyan Zhao ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Warburg Effect ◽  
Aerobic Glycolysis ◽  
Luciferase Reporter ◽  
Gastric Cancer Cells ◽  
Expression Levels ◽  
Cancer Tissues

Abstract Background Reprogrammed glucose metabolism of enhanced Warburg effect (or aerobic glycolysis) is considered as a hallmark of cancer. Long non-coding RNAs (lncRNAs) have been certified to play a crucial role in tumor progression. The current study aims to inquire into the potential regulatory mechanism of long intergenic non-protein coding RNA 242 (LINC00242) on aerobic glycolysis in gastric cancer. Method LINC00242, miR-1-3p and G6PD expression levels in gastric cancer tissues and cells were determined by qRT-PCR. Cell apoptosis or viability were examined by Flow cytometry or MTT assay. Western blot was utilized to investigate G6PD protein expression levels. Immunohistochemical (IHC) and hematoxylin and eosin (H&E) staining were used for histopathological detection. The targeted relationship between LINC00242 or G6PD and miR-1-3p was verified by luciferase reporter gene assay. Nude mouse xenograft was utilized to detect tumor formation in vivo. Result LINC00242 and G6PD was high-expressed in gastric cancer tissues and cells, and LINC00242 is positively correlated with G6PD. Silencing of LINC00242 or G6PD within gastric cancer cells prominently inhibited cell proliferation and aerobic glycolysis in vitro and relieved the tumorigenesis of gastric cancer in vivo. miR-1-3p was predicted to directly target both LINC00242 and G6PD. Overexpression of miR-1-3p suppressed gastric cancer cells proliferation and aerobic glycolysis. LINC00242 competitively combined miR-1-3p, therefore relieving miR-1-3p-mediated suppression on G6PD. Conclusion LINC00242 plays a stimulative role in gastric cancer aerobic glycolysis via regulation of miR-1-3p/ G6PD axis, therefore affecting gastric cancer cell proliferation.

scholarly journals Anti-Warburg Effect of Melatonin: A Proposed Mechanism to Explain its Inhibition of Multiple Diseases

2021 ◽  
Vol 22 (2) ◽  
pp. 764
Author(s):  
Russel J. Reiter ◽  
Ramaswamy Sharma ◽  
Sergio Rosales-Corral
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Warburg Effect ◽  
Coenzyme A ◽  
Aerobic Glycolysis ◽  
Pyruvate Dehydrogenase Complex ◽  
Pyruvate Dehydrogenase Kinase ◽  
Metabolic Phenotype ◽  
Common Denominator ◽  
Acetyl Coenzyme A ◽  
Acetyl Coenzyme

Glucose is an essential nutrient for every cell but its metabolic fate depends on cellular phenotype. Normally, the product of cytosolic glycolysis, pyruvate, is transported into mitochondria and irreversibly converted to acetyl coenzyme A by pyruvate dehydrogenase complex (PDC). In some pathological cells, however, pyruvate transport into the mitochondria is blocked due to the inhibition of PDC by pyruvate dehydrogenase kinase. This altered metabolism is referred to as aerobic glycolysis (Warburg effect) and is common in solid tumors and in other pathological cells. Switching from mitochondrial oxidative phosphorylation to aerobic glycolysis provides diseased cells with advantages because of the rapid production of ATP and the activation of pentose phosphate pathway (PPP) which provides nucleotides required for elevated cellular metabolism. Molecules, called glycolytics, inhibit aerobic glycolysis and convert cells to a healthier phenotype. Glycolytics often function by inhibiting hypoxia-inducible factor-1α leading to PDC disinhibition allowing for intramitochondrial conversion of pyruvate into acetyl coenzyme A. Melatonin is a glycolytic which converts diseased cells to the healthier phenotype. Herein we propose that melatonin’s function as a glycolytic explains its actions in inhibiting a variety of diseases. Thus, the common denominator is melatonin’s action in switching the metabolic phenotype of cells.

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