scholarly journals Rewiring glucose metabolism improves 5-FU efficacy in glycolytic p53-deficient colorectal tumors

2021 ◽  
Author(s):  
Marlies C. Ludikhuize ◽  
Sira Gevers ◽  
Nguyen T.B. Nguyen ◽  
Maaike Meerlo ◽  
S. Khadijeh Shafiei Roudbari ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Glucose Metabolism ◽  
Molecular Mechanisms ◽  
Cancer Metabolism ◽  
Genetically Engineered ◽  
Driver Mutations ◽  
Colorectal Tumors ◽  
Promising Strategy ◽  
The Warburg Effect

5-fluorouracil (5-FU) is the backbone for chemotherapy in colorectal cancer (CRC). Response rates in patients are, however, limited to 50%. The molecular mechanisms by which 5-FU induces toxicity remain unclear, limiting the development of strategies to improve efficacy. How fundamental aspects, such as driver mutations and intra-tumor heterogeneity, relate to the 5-FU response is ill-defined. Here, we analyzed the 5-FU response in human organoids genetically engineered to reproduce the different stages of CRC progression. We find that 5-FU induces pyrimidine imbalance, which leads to DNA damage and cell death. Proliferating cancer (stem) cells are, accordingly, efficiently targeted by 5-FU. Importantly, p53 behaves as a discriminating factor for 5-FU sensitivity, whereas p53-deficiency leads to DNA damage-induced cell death, active p53 protects from these effects. Moreover, we find that targeting the Warburg effect, by rewiring glucose metabolism, enhances 5-FU toxicity by further altering the nucleotide pool and without increasing toxicity in healthy-non-transformed cells. Thus, targeting cancer metabolism in combination with replication stress-inducing chemotherapies emerges as a promising strategy for CRC treatment.

scholarly journals Rewiring Glucose Metabolism Improves 5-FU Efficacy in Glycolytic p53-Deficient Colorectal Tumors

2021 ◽  
Author(s):  
Marlies Ludikhuize ◽  
Sira Gevers ◽  
Nguyen Nguyen ◽  
Maaike Meerlo ◽  
S. Khadijeh Shafiei Roudbari ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Glucose Metabolism ◽  
Molecular Mechanisms ◽  
Genetically Engineered ◽  
Driver Mutations ◽  
Cycle Arrest ◽  
Promising Strategy ◽  
Clinical Models ◽  
The Warburg Effect

Abstract 5-fluorouracil (5-FU) is the backbone for chemotherapy in colorectal cancer (CRC), however response rates in patients are limited to 50%. Unexpectedly, the molecular mechanisms by which 5-FU ultimately induces toxicity remain debated, limiting the development of strategies to improve its efficacy. How fundamental aspects of cancer, such as driver mutations and phenotypic intra-tumor heterogeneity, relate to the 5-FU response are ill-defined. This is largely due to a shortage of mechanistic studies in pre-clinical models able to recapitulate the key-features of CRC. Here, we analyzed the 5-FU response in human organoids genetically engineered to reproduce the different stages of CRC progression. We find that 5-FU induces pyrimidine imbalance, which leads to DNA damage and cell death. Actively proliferating cancer (stem) cells are, accordingly, efficiently targeted by 5-FU. Importantly, p53 behaves as a discriminating factor for 5-FU sensitivity, whereas p53-deficiency leads to DNA damage-induced cell death, active p53 protects from these effects through inducing cell cycle arrest. Moreover, we find that targeting the Warburg effect, by rewiring glucose metabolism, enhances 5-FU toxicity by altering the nucleotide pool and without increasing toxicity in non-transformed cells. Thus, rewiring glucose metabolism in combination with replication stress-inducing chemotherapies emerges as a promising strategy for CRC treatment.

scholarly journals Proton export drives the Warburg Effect

2021 ◽  
Author(s):  
Shonagh Russell ◽  
Liping Xu ◽  
Yoonseok Kam ◽  
Dominique Abrahams ◽  
Bryce Ordway ◽  
...  
Keyword(s):  
Warburg Effect ◽  
Cancer Metabolism ◽  
Aerobic Glycolysis ◽  
Lactate Production ◽  
Glycolytic Enzymes ◽  
Hek293 Cells ◽  
Driver Mutations ◽  
The Warburg Effect

Aggressive cancers commonly ferment glucose to lactic acid at high rates, even in the presence of oxygen. This is known as aerobic glycolysis, or the “Warburg Effect”. It is widely assumed that this is a consequence of the upregulation of glycolytic enzymes. Oncogenic drivers can increase the expression of most proteins in the glycolytic pathway, including the terminal step of exporting H+ equivalents from the cytoplasm. Proton exporters maintain an alkaline cytoplasmic pH, which can enhance all glycolytic enzyme activities, even in the absence of oncogene-related expression changes. Based on this observation, we hypothesized that increased uptake and fermentative metabolism of glucose could be driven by the expulsion of H+ equivalents from the cell. To test this hypothesis, we stably transfected lowly-glycolytic MCF-7, U2-OS, and glycolytic HEK293 cells to express proton exporting systems: either PMA1 (yeast H+-ATPase) or CAIX (carbonic anhydrase 9). The expression of either exporter in vitro enhanced aerobic glycolysis as measured by glucose consumption, lactate production, and extracellular acidification rate. This resulted in an increased intracellular pH, and metabolomic analyses indicated that this was associated with an increased flux of all glycolytic enzymes upstream of pyruvate kinase. These cells also demonstrated increased migratory and invasive phenotypes in vitro, and these were recapitulated in vivo by more aggressive behavior, whereby the acid-producing cells formed higher grade tumors with higher rates of metastases. Neutralizing tumor acidity with oral buffers reduced the metastatic burden. Therefore, cancer cells with increased H+ export increase intracellular alkalization, even without oncogenic driver mutations, and this is sufficient to alter cancer metabolism towards a Warburg phenotype.

scholarly journals Glucose Metabolism in Cancer: The Warburg Effect and Beyond

2021 ◽  
pp. 3-15 ◽  
Author(s):  
Sminu Bose ◽  
Cissy Zhang ◽  
Anne Le
Keyword(s):  
Glucose Metabolism ◽  
Molecular Biology ◽  
Warburg Effect ◽  
Scientific Community ◽  
Cancer Metabolism ◽  
Cancer Therapies ◽  
Otto Warburg ◽  
New Cancer Therapies ◽  
Open The Doors ◽  
The Warburg Effect

AbstractOtto Warburg observed a peculiar phenomenon in 1924, unknowingly laying the foundation for the field of cancer metabolism. While his contemporaries hypothesized that tumor cells derived the energy required for uncontrolled replication from proteolysis and lipolysis, Warburg instead found them to rapidly consume glucose, converting it to lactate even in the presence of oxygen. The significance of this finding, later termed the Warburg effect, went unnoticed by the broader scientific community at that time. The field of cancer metabolism lay dormant for almost a century awaiting advances in molecular biology and genetics, which would later open the doors to new cancer therapies [2, 3].

scholarly journals A Review and Rationale for the Use of Genetically Engineered Animals in the Study of Traumatic Brain Injury

2001 ◽  
Vol 21 (11) ◽  
pp. 1241-1258 ◽  
Author(s):  
Luca Longhi ◽  
Kathryn E. Saatman ◽  
Ramesh Raghupathi ◽  
Helmut L. Laurer ◽  
Philipp M. Lenzlinger ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Dna Damage ◽  
Cell Death ◽  
Brain Injury ◽  
Human Head ◽  
Genetically Engineered ◽  
Cellular Mechanisms ◽  
Cell Dysfunction ◽  
Damage Repair ◽  
Genetically Engineered Mice

The mechanisms underlying secondary cell death after traumatic brain injury (TBI) are poorly understood. Animal models of TBI recapitulate many clinical and pathologic aspects of human head injury, and the development of genetically engineered animals has offered the opportunity to investigate the specific molecular and cellular mechanisms associated with cell dysfunction and death after TBI, allowing for the evaluation of specific cause-effect relations and mechanistic hypotheses. This article represents a compendium of the current literature using genetically engineered mice in studies designed to better understand the posttraumatic inflammatory response, the mechanisms underlying DNA damage, repair, and cell death, and the link between TBI and neurodegenerative diseases.

scholarly journals Top1-PARP1 association and beyond: from DNA topology to break repair

NAR Cancer ◽  
2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Srijita Paul Chowdhuri ◽  
Benu Brata Das
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Molecular Mechanisms ◽  
Parp Inhibitors ◽  
Dna Topology ◽  
Molecular Network ◽  
Dna Breaks ◽  
Nuclear Dynamics ◽  
Topoisomerase 1 ◽  
Break Repair

Abstract Selective trapping of human topoisomerase 1 (Top1) on the DNA (Top1 cleavage complexes; Top1cc) by specific Top1-poisons triggers DNA breaks and cell death. Poly(ADP-ribose) polymerase 1 (PARP1) is an early nick sensor for trapped Top1cc. New mechanistic insights have been developed in recent years to rationalize the importance of PARP1 beyond the repair of Top1-induced DNA breaks. This review summarizes the progress in the molecular mechanisms of trapped Top1cc-induced DNA damage, PARP1 activation at DNA damage sites, PAR-dependent regulation of Top1 nuclear dynamics, and PARP1-associated molecular network for Top1cc repair. Finally, we have discussed the rationale behind the synergy between the combination of Top1 poison and PARP inhibitors in cancer chemotherapies, which is independent of the ‘PARP trapping’ phenomenon.

scholarly journals Targeting Ferroptosis for Lung Diseases: Exploring Novel Strategies in Ferroptosis-Associated Mechanisms

2021 ◽  
Vol 2021 ◽  
pp. 1-21
Author(s):  
Tian-Liang Ma ◽  
Yong Zhou ◽  
Ci Wang ◽  
Lu Wang ◽  
Jing-Xian Chen ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Membrane ◽  
Lung Diseases ◽  
Molecular Mechanisms ◽  
Membrane Rupture ◽  
Promising Strategy ◽  
Regulated Cell Death ◽  
Regulated Necrosis ◽  
Organelle Membrane ◽  
Long Chain

Ferroptosis is an iron-dependent regulated necrosis characterized by the peroxidation damage of lipid molecular containing unsaturated fatty acid long chain on the cell membrane or organelle membrane after cellular deactivation restitution system, resulting in the cell membrane rupture. Ferroptosis is biochemically and morphologically distinct and disparate from other forms of regulated cell death. Recently, mounting studies have investigated the mechanism of ferroptosis, and numerous proteins play vital roles in regulating ferroptosis. With detailed studies, emerging evidence indicates that ferroptosis is found in multiple lung diseases, demonstrating that ferroptosis appears to be particularly important for lung diseases. The mounting interest in ferroptosis drugs specifically targeting the ferroptosis mechanism holds substantial therapeutic promise in lung diseases. The present review emphatically summarizes the functions and integrated molecular mechanisms of ferroptosis in various lung diseases, proposing that multiangle regulation of ferroptosis might be a promising strategy for the clinical treatment of lung diseases.

Warburg and Krebs and related effects in cancer

2019 ◽  
Vol 21 ◽  
Author(s):  
Judith E. Unterlass ◽  
Nicola J. Curtin
Keyword(s):  
Glucose Metabolism ◽  
Cancer Metabolism ◽  
Therapeutic Potential ◽  
Genetic Alterations ◽  
Therapeutic Strategies ◽  
Metabolic Phenotype ◽  
Altered Glucose ◽  
Essential Nutrient ◽  
Cell Glucose ◽  
The Warburg Effect

AbstractWarburg and coworkers' observation of altered glucose metabolism in tumours has been neglected for several decades, which, in part, was because of an initial misinterpretation of the basis of their finding. Following the realisation that genetic alterations are often linked to metabolism, and that the tumour micro-environment imposes different demands on cancer cells, has led to a reinvestigation of cancer metabolism in recent years. Increasing our understanding of the drivers and consequences of the Warburg effect in cancer and beyond will help to identify new therapeutic strategies as well as to identify new prognostic and therapeutic biomarkers. Here we discuss the initial findings of Warburg and coworkers regarding cancer cell glucose metabolism, how these studies came into focus again in recent years following the discovery of metabolic oncogenes, and the therapeutic potential that lies within targeting the altered metabolic phenotype in cancer. In addition, another essential nutrient in cancer metabolism, glutamine, will be discussed.

scholarly journals Apoptosis, the only cell death pathway that can be measured in human diploid dermal fibroblasts following lethal UVB irradiation

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Anne-Sophie Gary ◽  
Patrick J. Rochette
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Dermal Fibroblasts ◽  
Driver Mutations ◽  
Uvb Irradiation ◽  
Cancer Driver ◽  
Cell Death Pathways ◽  
Cell Death Pathway ◽  
Cellular Metabolic Activity

Abstract Ultraviolet radiation (UVR) is a major environmental genotoxic agent. In skin, it can lead to the formation of mutagenic DNA damage. Several mechanisms are in place to prevent the conversion of these DNA damage into skin cancer-driver mutations. An important mutation prevention mechanism is the programmed cell death, which can safely dispose of the damaged cells. Apoptosis is the most studied and best characterised programmed cell death, but an increasing amount of new cell death pathways are emerging. Using different pharmacological cell death inhibitors and antioxidants, we have evaluated the implication of apoptosis, necroptosis, ferroptosis and parthanatos in UVB-induced cell death in human diploid dermal fibroblasts. Our results show that apoptosis is the only known cell death mechanism induced by UVB irradiation in fibroblasts. We also showed that lethal UVB irradiation induces a PARP-dependent drastic loss of cellular metabolic activity caused by an overused of NAD+.

scholarly journals Ferroptosis in Lung Cancer: From Molecular Mechanisms to Prognostic and Therapeutic Opportunities

2021 ◽  
Vol 11 ◽  
Author(s):  
Peyman Tabnak ◽  
Zanyar HajiEsmailPoor ◽  
Soroush Soraneh
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Molecular Mechanisms ◽  
Dependent Manner ◽  
Oxygen Species ◽  
Radical Oxygen Species ◽  
Future Studies ◽  
New Horizons ◽  
The Road ◽  
Promising Strategy

Lung cancer is the second commonly diagnosed malignancy worldwide and has the highest mortality rate among all cancers. Tremendous efforts have been made to develop novel strategies against lung cancer; however, the overall survival of patients still is low. Uncovering underlying molecular mechanisms of this disease can open up new horizons for its treatment. Ferroptosis is a newly discovered type of programmed cell death that, in an iron-dependent manner, peroxidizes unsaturated phospholipids and results in the accumulation of radical oxygen species. Subsequent oxidative damage caused by ferroptosis contributes to cell death in tumor cells. Therefore, understanding its molecular mechanisms in lung cancer appears as a promising strategy to induce ferroptosis selectively. According to evidence published up to now, significant numbers of research have been done to identify ferroptosis regulators in lung cancer. Therefore, this review aims to provide a comprehensive standpoint of molecular mechanisms of ferroptosis in lung cancer and address these molecules’ prognostic and therapeutic values, hoping that the road for future studies in this field will be paved more efficiently.

scholarly journals Aberrant Expression of the Transcription Factors Snail and Slug Alters the Response to Genotoxic Stress

2004 ◽  
Vol 24 (17) ◽  
pp. 7559-7566 ◽  
Author(s):  
Masahiro Kajita ◽  
Karissa N. McClinic ◽  
Paul A. Wade
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Molecular Mechanisms ◽  
Human Cancer ◽  
Genotoxic Stress ◽  
Growth Potential ◽  
Invasive Growth ◽  
Aberrant Expression ◽  
Cell Cell

ABSTRACT Snail and Slug are closely related transcriptional repressors involved in embryonic patterning during metazoan development. In human cancer, aberrant expression of Snail and/or Slug has been correlated with invasive growth potential, a property primarily attributed to their ability to directly repress transcription of genes whose products are involved in cell-cell adhesion, such as E-cadherin, occludin, and claudins. To investigate the molecular mechanisms of alterations in epithelial cell fate mediated by aberrant expression of Snail or Slug, we analyzed the consequences of exogenous expression of these factors in human cancer cells. Aberrant expression of either Snail or Slug led to changes in cell morphology, the loss of normal cell-cell contacts, and the acquisition of invasive growth properties. Snail or Slug expression also promoted resistance to programmed cell death elicited by DNA damage. Detailed molecular analysis revealed direct transcriptional repression of multiple factors with well-documented roles in programmed cell death. Depletion of endogenous Snail by RNA interference led to increased sensitivity to DNA damage accompanied by increased expression of the proapoptotic factors identified as targets of Snail. Thus, aberrant expression of Snail or Slug may promote tumorigenesis through increased resistance to programmed cell death.

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