scholarly journals Genetic Mutations and Non-Coding RNA-Based Epigenetic Alterations Mediating the Warburg Effect in Colorectal Carcinogenesis

Biology ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 847
Author(s):  
Batoul Abi Zamer ◽  
Wafaa Abumustafa ◽  
Mawieh Hamad ◽  
Azzam A. Maghazachi ◽  
Jibran Sualeh Muhammad
Keyword(s):  
Colorectal Cancer ◽  
Glucose Metabolism ◽  
Warburg Effect ◽  
Colorectal Carcinogenesis ◽  
Genetic Mutations ◽  
Epigenetic Alterations ◽  
Therapeutic Approaches ◽  
Non Coding Rna ◽  
Gradual Process ◽  
The Warburg Effect

Colorectal cancer (CRC) development is a gradual process defined by the accumulation of numerous genetic mutations and epigenetic alterations leading to the adenoma-carcinoma sequence. Despite significant advances in the diagnosis and treatment of CRC, it continues to be a leading cause of cancer-related deaths worldwide. Even in the presence of oxygen, CRC cells bypass oxidative phosphorylation to produce metabolites that enable them to proliferate and survive—a phenomenon known as the “Warburg effect”. Understanding the complex glucose metabolism in CRC cells may support the development of new diagnostic and therapeutic approaches. Here we discuss the most recent findings on genetic mutations and epigenetic modulations that may positively or negatively regulate the Warburg effect in CRC cells. We focus on the non-coding RNA (ncRNA)-based epigenetics, and we present a perspective on the therapeutic relevance of critical molecules and ncRNAs mediating the Warburg effect in CRC cells. All the relevant studies were identified and assessed according to the genes and enzymes mediating the Warburg effect. The findings summarized in this review should provide a better understanding of the relevance of genetic mutations and the ncRNA-based epigenetic alterations to CRC pathogenesis to help overcome chemoresistance.

scholarly journals Insulin-Like Growth Factor 1 (IGF-1) Signaling in Glucose Metabolism in Colorectal Cancer

2021 ◽  
Vol 22 (12) ◽  
pp. 6434
Author(s):  
Aldona Kasprzak
Keyword(s):  
Colorectal Cancer ◽  
Growth Factor ◽  
Glucose Metabolism ◽  
Warburg Effect ◽  
Mapk Signaling ◽  
Colorectal Carcinogenesis ◽  
Insulin Like Growth Factor ◽  
Aberrant Expression ◽  
The Warburg Effect

Colorectal cancer (CRC) is one of the most common aggressive carcinoma types worldwide, characterized by unfavorable curative effect and poor prognosis. Epidemiological data re-vealed that CRC risk is increased in patients with metabolic syndrome (MetS) and its serum components (e.g., hyperglycemia). High glycemic index diets, which chronically raise post-prandial blood glucose, may at least in part increase colon cancer risk via the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway. However, the underlying mechanisms linking IGF-1 and MetS are still poorly understood. Hyperactivated glucose uptake and aerobic glycolysis (the Warburg effect) are considered as a one of six hallmarks of cancer, including CRC. However, the role of insulin/IGF-1 signaling during the acquisition of the Warburg metabolic phenotypes by CRC cells is still poorly understood. It most likely results from the interaction of multiple processes, directly or indirectly regulated by IGF-1, such as activation of PI3K/Akt/mTORC, and Raf/MAPK signaling pathways, activation of glucose transporters (e.g., GLUT1), activation of key glycolytic enzymes (e.g., LDHA, LDH5, HK II, and PFKFB3), aberrant expression of the oncogenes (e.g., MYC, and KRAS) and/or overexpression of signaling proteins (e.g., HIF-1, TGF-β1, PI3K, ERK, Akt, and mTOR). This review describes the role of IGF-1 in glucose metabolism in physiology and colorectal carcinogenesis, including the role of the insulin/IGF system in the Warburg effect. Furthermore, current therapeutic strategies aimed at repairing impaired glucose metabolism in CRC are indicated.

F. nucleatum targets lncRNA ENO1-IT1 to promote glycolysis and oncogenesis in colorectal cancer

Gut ◽  
2020 ◽  
pp. gutjnl-2020-322780
Author(s):  
Jie Hong ◽  
Fangfang Guo ◽  
Shi-Yuan Lu ◽  
Chaoqin Shen ◽  
Dan Ma ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Glucose Metabolism ◽  
Target Genes ◽  
Colorectal Carcinogenesis ◽  
Pcr Analysis ◽  
Positron Emission ◽  
Non Coding Rna ◽  
Cancer Models ◽  
Chromatin Immunoprecipitation Sequencing ◽  
Rna Immunoprecipitation

ObjectiveMicrobiota disorder promotes chronic inflammation and carcinogenesis. High glycolysis is associated with poor prognosis in patients with colorectal cancer (CRC). However, the potential correlation between the gut microbiota and glucose metabolism is unknown in CRC.Design18F-FDG (18F-fluorodeoxyglucose) PET (positron emission tomography)/CT image scanning data and microbiota PCR analysis were performed to measure the correlation between metabolic alterations and microbiota disorder in 33 patients with CRC. Multiple colorectal cancer models, metabolic analysis and Seahorse assay were established to assess the role of long non-coding RNA (lncRNA) enolase1-intronic transcript 1 (ENO1-IT1) in Fusobacterium (F.) nucleatum-induced glucose metabolism and colorectal carcinogenesis. RNA immunoprecipitation and chromatin immunoprecipitation sequencing were conducted to identify potential targets of lncRNA ENO1-IT1.ResultsWe have found F. nucleatum abundance correlated with high glucose metabolism in patients with CRC. Furthermore, F. nucleatum supported carcinogenesis via increasing CRC cell glucose metabolism. Mechanistically, F. nucleatum activated lncRNA ENO1-IT1 transcription via upregulating the binding efficiency of transcription factor SP1 to the promoter region of lncRNA ENO1-IT1. Elevated ENO1-IT behaved as a guider modular for KAT7 histone acetyltransferase, specifying the histone modification pattern on its target genes, including ENO1, and consequently altering CRC biological function.ConclusionF. nucleatum and glucose metabolism are mechanistically, biologically and clinically connected to CRC. Targeting ENO1 pathway may be meaningful in treating patients with CRC with elevated F. nucleatum.

scholarly journals Iron Regulates the Warburg Effect and Ferroptosis in Colorectal Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Yin Yuan ◽  
Shuo Ni ◽  
Aoxiang Zhuge ◽  
Bo Li ◽  
Lanjuan Li
Keyword(s):  
Colorectal Cancer ◽  
Warburg Effect ◽  
Related Factor ◽  
Nuclear Factor ◽  
Oxygen Species ◽  
Therapeutic Approaches ◽  
Enhanced Resistance ◽  
The Warburg Effect

Iron promotes the proliferation of cancer cells, but it also contributes to cell death. Here we explored whether iron could promote the Warburg effect of colorectal cancer (CRC) cells and suppress sensitivity to ferroptosis by inducing reactive oxygen species (ROS) and regulating nuclear factor erythroid 2-related factor 2 (NRF2). In this study, cell proliferation abilities were measured by CCK-8, EdU incorporation, and colony formation assays. Seahorse XF96 respirometry assays were used to detect the Warburg effect and the level of ROS was assess by DCFH-DA fluorescent probes. Results showed that iron exposure promoted the Warburg effect of CRC cells by inducing ROS and activating NRF2 both in vivo and in vitro. In addition, iron exposure also induced ferroptosis in CRC cells, but at the same time its inhibitory proteins SLC7A11 and GPX4 were also upregulated, indicating an enhanced resistance to ferroptosis. Our results revealed that iron can effectively promote tumorigenesis. Meanwhile, iron elimination or a low-iron diet might be valid therapeutic approaches for CRC.

scholarly journals LAT1 and ASCT2 Related microRNAs as Potential New Therapeutic Agents against Colorectal Cancer Progression

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 195
Author(s):  
Francisca Dias ◽  
Cristina Almeida ◽  
Ana Luísa Teixeira ◽  
Mariana Morais ◽  
Rui Medeiros
Keyword(s):  
Colorectal Cancer ◽  
Amino Acid ◽  
Cancer Progression ◽  
Cell Metabolism ◽  
Tumor Development ◽  
Amino Acid Transporters ◽  
Epigenetic Alterations ◽  
Therapeutic Approaches ◽  
Colorectal Cancer Progression ◽  
Made In

The development and progression of colorectal cancer (CRC) have been associated with genetic and epigenetic alterations and more recently with changes in cell metabolism. Amino acid transporters are key players in tumor development, and it is described that tumor cells upregulate some AA transporters in order to support the increased amino acid (AA) intake to sustain the tumor additional needs for tumor growth and proliferation through the activation of several signaling pathways. LAT1 and ASCT2 are two AA transporters involved in the regulation of the mTOR pathway that has been reported as upregulated in CRC. Some attempts have been made in order to develop therapeutic approaches to target these AA transporters, however none have reached the clinical setting so far. MiRNA-based therapies have been gaining increasing attention from pharmaceutical companies and now several miRNA-based drugs are currently in clinical trials with promising results. In this review we combine a bioinformatic approach with a literature review in order to identify a miRNA profile with the potential to target both LAT1 and ASCT2 with potential to be used as a therapeutic approach against CRC.

scholarly journals Promotion of the Warburg effect is associated with poor benefit from adjuvant chemotherapy in colorectal cancer

2020 ◽  
Vol 111 (2) ◽  
pp. 658-666
Author(s):  
Masashi Kitazawa ◽  
Tomohisa Hatta ◽  
Yusuke Sasaki ◽  
Kazuhiko Fukui ◽  
Koji Ogawa ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Adjuvant Chemotherapy ◽  
Warburg Effect ◽  
The Warburg Effect

Su2027 Mitochondrial Dysregulation in Premalignant Colonic Epithelium: Evidence of the Warburg Effect During Initiation of Colorectal Carcinogenesis

2016 ◽  
Vol 150 (4) ◽  
pp. S615
Author(s):  
Mart DeLaCruz ◽  
Jonathan T. Ohm ◽  
Bilal Latif ◽  
Audrey H. Calderwood ◽  
Navneet Momi ◽  
...  
Keyword(s):  
Warburg Effect ◽  
Colorectal Carcinogenesis ◽  
Colonic Epithelium ◽  
The Warburg Effect

scholarly journals Colorectal Cancer: From the Genetic Model to Posttranscriptional Regulation by Noncoding RNAs

2017 ◽  
Vol 2017 ◽  
pp. 1-38 ◽  
Author(s):  
María Antonia Lizarbe ◽  
Jorge Calle-Espinosa ◽  
Eva Fernández-Lizarbe ◽  
Sara Fernández-Lizarbe ◽  
Miguel Ángel Robles ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Posttranscriptional Regulation ◽  
Genetic Model ◽  
Treatment Options ◽  
Noncoding Rnas ◽  
Developed Countries ◽  
Colorectal Carcinogenesis ◽  
Special Focus ◽  
Epigenetic Alterations ◽  
And Function

Colorectal cancer is the third most common form of cancer in developed countries and, despite the improvements achieved in its treatment options, remains as one of the main causes of cancer-related death. In this review, we first focus on colorectal carcinogenesis and on the genetic and epigenetic alterations involved. In addition, noncoding RNAs have been shown to be important regulators of gene expression. We present a general overview of what is known about these molecules and their role and dysregulation in cancer, with a special focus on the biogenesis, characteristics, and function of microRNAs. These molecules are important regulators of carcinogenesis, progression, invasion, angiogenesis, and metastases in cancer, including colorectal cancer. For this reason, miRNAs can be used as potential biomarkers for diagnosis, prognosis, and efficacy of chemotherapeutic treatments, or even as therapeutic agents, or as targets by themselves. Thus, this review highlights the importance of miRNAs in the development, progression, diagnosis, and therapy of colorectal cancer and summarizes current therapeutic approaches for the treatment of colorectal cancer.

scholarly journals Hyperbaric Oxygen Therapy Represses the Warburg Effect and Epithelial–Mesenchymal Transition in Hypoxic NSCLC Cells via the HIF-1α/PFKP Axis

2021 ◽  
Vol 11 ◽  
Author(s):  
Linling Zhang ◽  
Jingjing Ke ◽  
Shengping Min ◽  
Nan Wu ◽  
Fei Liu ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Cell Lines ◽  
Hyperbaric Oxygen ◽  
Hyperbaric Oxygen Therapy ◽  
Warburg Effect ◽  
Oxygen Therapy ◽  
Nsclc Cell ◽  
Glycolytic Flux ◽  
Mesenchymal Transition ◽  
The Warburg Effect

BackgroundTumor cells initiate hypoxia-induced mechanisms to fuel cell proliferation, invasion, and metastasis, largely mediated by low O2-responsive Hypoxia-Inducible Factor 1 Alpha (HIF-1α). Therefore, hyperbaric oxygen therapy (HBO) is now being studied in cancer patients, but its impact upon non-small-cell lung cancer (NSCLC) cell metabolism remains uncharacterized.MethodsWe employed the NSCLC cell lines A549 and H1299 for in vitro studies. Glucose uptake, pyruvate, lactate, and adenosine triphosphate (ATP) assays were used to assess aerobic glycolysis (Warburg effect). A quantitative glycolytic flux model was used to analyze the flux contributions of HIF-1α-induced glucose metabolism genes. We used a Lewis lung carcinoma (LLC) murine model to measure lung tumorigenesis in C57BL/6J mice.ResultsHBO suppressed hypoxia-induced HIF-1α expression and downstream HIF-1α signaling in NSCLC cells. One HIF-1α-induced glucose metabolism gene—Phosphofructokinase, Platelet (PFKP)—most profoundly enhanced glycolytic flux under both low- and high-glucose conditions. HBO suppressed hypoxia-induced PFKP transactivation and gene expression via HIF-1α downregulation. HBO’s suppression of the Warburg effect, suppression of hyperproliferation, and suppression of epithelial-to-mesenchymal transition (EMT) in hypoxic NSCLC cell lines is mediated by the HIF-1α/PFKP axis. In vivo, HBO therapy inhibited murine LLC lung tumor growth in a Pfkp-dependent manner.ConclusionsHBO’s repression of the Warburg effect, repression of hyperproliferation, and repression of EMT in hypoxic NSCLC cells is dependent upon HIF-1α downregulation. HIF-1α’s target gene PFKP functions as a central mediator of HBO’s effects in hypoxic NSCLC cells and may represent a metabolic vulnerability in NSCLC tumors.

scholarly journals Dysfunction of an energy sensor NFE2L1 triggers uncontrollable AMPK signal and glucose metabolism reprogramming

2021 ◽  
Author(s):  
Qiufang Yang ◽  
Wenshan Zhao ◽  
Yadi Xing ◽  
Peng Li ◽  
Xiaowen Zhou ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Warburg Effect ◽  
Metabolic Diseases ◽  
Energy State ◽  
Glucose Deprivation ◽  
Cancer Development ◽  
Energy Sensor ◽  
Dual Sensor ◽  
Glycolysis Pathway ◽  
The Warburg Effect

AbstractNFE2L1 (also called Nrf1) acts a core regulator of redox signaling and metabolism homeostasis, and thus its dysfunction results in multiple systemic metabolic diseases. However, the molecular mechanism(s) by which NFE2L1 regulates glycose and lipid metabolism is still elusive. Here, we found that the loss of NFE2L1 in human HepG2 cells led to a lethal phenotype upon glucose deprivation. The uptake of glucose was also affected by NFE2L1 deficiency. Further experiments unveiled that although the glycosylation of NFE2L1 was monitored through the glycolysis pathway, it enabled to sense the energy state and directly interacted with AMPK. These indicate that NFE2L1 can serve as a dual sensor and regulator of glucose homeostasis. In-depth sights into transcriptome, metabolome and seahorse data further unraveled that glucose metabolism was reprogrammed by disruption of NFE2L1, so as to aggravate the Warburg effect in NFE2L1-silenced hepatoma cells, along with the mitochondrial damage observed under the electron microscope. Collectively, these demonstrate that disfunction of NFE2L1 triggers the uncontrollable signaling by AMPK towards glucose metabolism reprogramming in the liver cancer development.

scholarly journals Head and Neck Squamous Cell Carcinoma: Epigenetic Landscape

Diagnostics ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 34
Author(s):  
Kamila Romanowska ◽  
Agnieszka Sobecka ◽  
Agnieszka A. Rawłuszko-Wieczorek ◽  
Wiktoria M. Suchorska ◽  
Wojciech Golusiński
Keyword(s):  
Head And Neck ◽  
Squamous Cell ◽  
Current Knowledge ◽  
Squamous Carcinoma ◽  
Genetic Mutations ◽  
Epigenetic Alterations ◽  
Intercellular Signaling ◽  
Epigenetic Landscape ◽  
Non Coding Rna ◽  
Clinical Surveillance

Head and neck squamous carcinoma (HNSCC) constitutes the sixth most prevalent cancer worldwide. The molecular pathogenesis of HNSCC includes disorders in cell cycle, intercellular signaling, proliferation, squamous cell differentiation and apoptosis. In addition to the genetic mutations, changes in HNSCC are also characterized by the accumulation of epigenetic alterations such as DNA methylation, histone modifications, non-coding RNA activity and RNA methylation. In fact, some of them may promote cancer formation and progression by controlling the gene expression machinery, hence, they could be used as biomarkers in the clinical surveillance of HNSCC or as targets for therapeutic strategies. In this review, we focus on the current knowledge regarding epigenetic modifications observed in HNSCC and its predictive value for cancer development.

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