The emerging role of glycolysis and immune evasion in gastric cancer DOI Creative Commons
Shanshan Zheng, Huai Li, Yaqi Li

et al.

Cancer Cell International, Journal Year: 2023, Volume and Issue: 23(1)

Published: Dec. 9, 2023

Abstract Gastric cancer (GC) is the fifth most common malignancy and third leading cause of cancer-related deaths worldwide. Similar to other types tumors, GC cells undergo metabolic reprogramming switch a “predominantly glycolytic” pattern promote its survival metastasis, also known as “the Warburg effect”, which characterized by enhanced glucose uptake lactate production. A large number studies have shown that targeting glycolysis promising strategy, can make more susceptible conventional treatment methods treatment, including chemotherapy, radiotherapy immunotherapy, so on. Therefore, this review summarizes characteristics in focuses on how abnormal concentration lead immunosuppression through effects differentiation, metabolism, function infiltrating immune cells, phenomenon may be potential strategy improve therapeutic efficacy GC.

Language: Английский

Targeting autophagy in obesity: from pathophysiology to management DOI
Yingmei Zhang, James R. Sowers, Jun Ren

et al.

Nature Reviews Endocrinology, Journal Year: 2018, Volume and Issue: 14(6), P. 356 - 376

Published: April 23, 2018

Language: Английский

Citations

304
Elucidating cancer metabolic plasticity by coupling gene regulation with metabolic pathways DOI Open Access
Dongya Jia, Mingyang Lu,

Kwang Hwa Jung

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2019, Volume and Issue: 116(9), P. 3909 - 3918

Published: Feb. 7, 2019

Metabolic plasticity enables cancer cells to switch their metabolism phenotypes between glycolysis and oxidative phosphorylation (OXPHOS) during tumorigenesis metastasis. However, it is still largely unknown how orchestrate gene regulation balance OXPHOS activities. Previously, by modeling the of we have reported that can acquire a stable hybrid metabolic state in which both be used. Here, comprehensively characterize activity, establish theoretical framework coupling with pathways. Our results demonstrate direct association activities AMPK HIF-1, master regulators glycolysis, respectively, three major pathways: glucose oxidation, fatty acid oxidation. model further characterizes metabolically inactive where low activity OXPHOS. We verify prediction using metabolomics transcriptomics data from paired tumor adjacent benign tissue samples cohort breast patients RNA-sequencing The Cancer Genome Atlas. validate vitro studies aggressive triple-negative (TNBC) cells. experimental confirm TNBC maintain phenotype targeting necessary eliminate plasticity. In summary, our work serves as platform symmetrically study tuning modulates pathway vice versa.

Language: Английский

Citations

279
The Warburg effect and drug resistance DOI Creative Commons
Bhaskar Bhattacharya,

Mohd Feroz Mohd Omar,

Richie Soong

et al.

British Journal of Pharmacology, Journal Year: 2016, Volume and Issue: 173(6), P. 970 - 979

Published: Jan. 11, 2016

: The Warburg effect describes the increased utilization of glycolysis rather than oxidative phosphorylation by tumour cells for their energy requirements under physiological oxygen conditions. This has been basis much speculation on survival advantage cells, tumourigenesis and microenvironment tumours. More recently, studies have begun to reveal how could influence drug efficacy our understanding energetics be exploited improve development. In particular, evidence is emerging demonstrating better modelling metabolic lead a prediction identification new combination strategies. review will provide details current complex interplay between glucose metabolism pharmacology discuss opportunities utilizing in future

Language: Английский

Citations

264
The lncRNA MACC1-AS1 promotes gastric cancer cell metabolic plasticity via AMPK/Lin28 mediated mRNA stability of MACC1 DOI Creative Commons
Yang Zhao, Yajing Liu, Lin Li

et al.

Molecular Cancer, Journal Year: 2018, Volume and Issue: 17(1)

Published: March 6, 2018

Metabolic plasticity has been increasingly thought to be a determinant of tumor growth and metastasis. MACC1, transcriptional regulator MET, was recognized as an oncogene in gastric cancer (GC); however, its or post-translational regulation not clear. We previously reported the metabolic role MACC1 glycolysis promote GC progression. MACC1-AS1 is antisense lncRNA yet function unknown. profiled analyzed expression utilizing TCGA database well situ hybridization using 123 pairs tissues matched adjacent normal mucosa (ANTs). The biological cell metastasis determined by performing vitro vivo functional experiments. Glycolysis antioxidant capabilities were assayed examine function. Further, specific regulatory effect on explored transcriptionally post-transcriptionally. shown expressed significantly higher than ANTs, which predicted poor prognosis patients. promoted proliferation inhibited apoptosis under stress. Mechanistically, stabilized mRNA post-transcriptionally augmented expression. mediate through upregulation subsequent enhanced anti-oxidative capabilities, this suggested coordinated AMPK/Lin28 pathway. Elevated linked promotes malignant phenotype upon cells. elevated stress facilitates promoting stabilization. Our study implicates valuable biomarker for diagnosis prognosis.

Language: Английский

Citations

212
Enhancing antitumor efficacy of CLDN18.2-directed antibody-drug conjugates through autophagy inhibition in gastric cancer DOI Creative Commons

Wenjing Xue,

Caili Xu,

Kaiqi Zhang

et al.

Cell Death Discovery, Journal Year: 2024, Volume and Issue: 10(1)

Published: Sept. 3, 2024

Abstract Claudin18.2 (CLDN18.2) is overexpressed in cancers of the digestive system, rendering it an ideal drug target for antibody-drug conjugates (ADCs). Despite many CLDN18.2-directed ADCs undergoing clinical trials, inconclusive underlying mechanisms pose a hurdle to extending utility these agents. In our study, αCLDN18.2-MMAE, ADC composed anti-CLDN18.2 monoclonal antibody and tubulin inhibitor MMAE, induced dose-dependent apoptosis via cleavage caspase-9/PARP proteins CLDN18.2-positive gastric cancer cells. It was worth noting that autophagy remarkably activated during αCLDN18.2-MMAE treatment, which characterized by accumulation autophagosomes, conversion marker LC3 from its form I II, complete autophagic flux. Inhibiting LY294002 enhanced αCLDN18.2-MMAE-induced cytotoxicity caspase-mediated apoptosis, indicating cytoprotective role ADC-treated Combination with significantly potentiated vivo antitumoral efficacy αCLDN18.2-MMAE. Besides, Akt/mTOR pathway inactivation demonstrated be implicated initiation αCLDN18.2-MMAE-treated conclusion, study highlighted groundbreaking investigation into mechanism ADC, focusing on crucial autophagy, providing novel insight treat combination inhibitor.

Language: Английский

Citations

22
Enolase 1 stimulates glycolysis to promote chemoresistance in gastric cancer DOI Open Access

Xiaoling Qian,

Wenxia Xu,

Jinye Xu

et al.

Oncotarget, Journal Year: 2017, Volume and Issue: 8(29), P. 47691 - 47708

Published: May 15, 2017

Chemotherapy is the major choice for cancer treatment of early and advanced stages. However, intrinsic or acquired drug resistance significantly restricts clinical efficacy chemotherapy. It critical to develop novel approaches detect overcome resistance. In this study, we demonstrated that accelerated glycolysis played a pivotal role in both cisplatin-resistance gastric cells. The metabolic reprogramming cisplatin-resistant cells was characterized by increased dependence. Inhibition with glucose starvation 2-Deoxy-D-glucose (2-DG) reversed By proteomic screening, found expression glycolytic enzyme Enolase 1 (ENO1) Depletion ENO1 siRNA reduced Moreover, attributed down-regulation ENO1-targeting miR-22, rather than activated gene transcriptional prolonged protein stability. Finally, elevated levels proteins were associated shorter overall survival patients. conclusion, biomarker predict prognosis cancer. Targeting chemical inhibitors up-regulating miR-22 could be valuable

Language: Английский

Citations

121
Glucose metabolism in gastric cancer: The cutting-edge DOI Creative Commons
Lianwen Yuan

World Journal of Gastroenterology, Journal Year: 2016, Volume and Issue: 22(6), P. 2046 - 2046

Published: Jan. 1, 2016

Glucose metabolism in gastric cancer cells differs from that of normal epithelial cells.Upregulated aerobic glycolysis (Warburg effect) meeting the demands cell proliferation is associated with genetic mutations, epigenetic modification and proteomic alteration.Understanding mechanisms may contribute to our knowledge carcinogenesis.Metabolomic studies offer novel, convenient practical tools search for new biomarkers early detection, diagnosis, prognosis, chemosensitivity prediction cancer.Interfering process provide a promising therapeutic strategy cancer.In this article, we present brief review recent glucose cancer, primary focus on clinical applications their potential role cancer.

Language: Английский

Citations

106
Knockdown of LncRNA‐UCA1 suppresses chemoresistance of pediatric AML by inhibiting glycolysis through the microRNA‐125a/hexokinase 2 pathway DOI
Yuan Zhang, Yufeng Liu,

Xueju Xu

et al.

Journal of Cellular Biochemistry, Journal Year: 2018, Volume and Issue: 119(7), P. 6296 - 6308

Published: April 16, 2018

Abstract Dysregulation of lncRNAs is implicated in chemoresistance varieties tumor including acute myeloid leukemia (AML). LncRNA urothelial carcinoma‐associated 1 (UCA1) was reported to play an oncogenic role AML. However, whether UCA1 involved pediatric AML remains unclear. expression patients after adriamycin (ADR)‐based chemotherapy and ADR‐resistant cells examined by qRT‐PCR. The effects on the cytotoxicity ADR glycolysis were evaluated MTT assay measuring glucose consumption lactate production HL60 HL60/ADR cells, repectively. protein levels hypoxia‐inducible factor 1α (HIF‐1α) hexokinase 2 (HK2) determined Western blot. Luciferase reporter RNA immunoprecipitation (RIP) used confirm relationships between UCA1, HK2, miR‐125a. We found that upregulated following ADR‐based chemotherapy. Knockdown increased cytotoxic effect inhibited HIF‐1α‐dependent cells. Additionally, functioned as a ceRNA miR‐125a directly binding target miR‐125a, positively regulated More notably, overexpression overturned miR‐125‐mediated inhibition Furthermore, 2‐deoxy‐glucose (2‐DG) exposure glycolysis, attenuated UCA1‐induced increase conclude knockdown plays positive overcoming AML, through suppressing miR‐125a/HK2 pathway, contributing better understanding molecular mechanism

Language: Английский

Citations

105
Dichloroacetate restores colorectal cancer chemosensitivity through the p53/miR-149-3p/PDK2-mediated glucose metabolic pathway DOI Creative Commons
Yu Liang, Lidan Hou, Linjing Li

et al.

Oncogene, Journal Year: 2019, Volume and Issue: 39(2), P. 469 - 485

Published: Oct. 9, 2019

Abstract The development of chemoresistance remains a major challenge that accounts for colorectal cancer (CRC) lethality. Dichloroacetate (DCA) was originally used as metabolic regulator in the treatment diseases; here, DCA assayed to identify mechanisms underlying CRC. We found markedly enhanced chemosensitivity CRC cells fluorouracil (5-FU), and reduced colony formation due high levels apoptosis. Using microarray assay, we noted miR-149-3p involved CRC, which modulated by wild-type p53 after treatment. In addition, PDK2 identified direct target miR-149-3p. Mechanistic analyses showed overexpression 5-FU-induced apoptosis glucose metabolism, similar effects knockdown. partially reversed inhibitory effect on metabolism. Finally, both 5-FU-resistant were sensitize chemotherapeutic 5-FU vivo, this also validated small retrospective cohort patients. Taken together, determined p53/miR-149-3p/PDK2 signaling pathway can potentially be targeted with overcome chemoresistant

Language: Английский

Citations

92
Expression of glycolytic enzymes in ovarian cancers and evaluation of the glycolytic pathway as a strategy for ovarian cancer treatment DOI Creative Commons
Chrysi Xintaropoulou, Carol Ward,

Alan Wise

et al.

BMC Cancer, Journal Year: 2018, Volume and Issue: 18(1)

Published: June 5, 2018

Novel therapeutic approaches are required to treat ovarian cancer and dependency on glycolysis may provide new targets for treatment. This study sought investigate the variation of expression molecular components (GLUT1, HKII, PKM2, LDHA) glycolytic pathway in cancers effectiveness targeting this cell lines with inhibitors. Expression GLUT1, LDHA were analysed by quantitative immunofluorescence a tissue microarray (TMA) analysis 380 associations clinicopathological features sought. The effect inhibitors growth panel was assessed use SRB proliferation assay. Combination studies undertaken combining these cytotoxic agents. Mean levels GLUT1 HKII higher high grade serous (HGSOC), most frequently occurring subtype, than non-HGSOC. also significantly advanced stage (III/IV) early (I/II) disease. Growth cells glucose demonstrated lines. Inhibitors (STF31, IOM-1190, 3PO oxamic acid) attenuated platinum-sensitive platinum-resistant HGSOC line models concentration dependent manner. In combination either cisplatin or paclitaxel, (a novel PFKFB3 inhibitor) enhanced both platinum sensitive resistant cells. Furthermore, synergy identified between STF31 acid (an LDH when combined metformin, an inhibitor oxidative phosphorylation, resulting marked inhibition growth. findings further support several useful combinations identified.

Language: Английский

Citations

90