INTERNATIONAL CONGRESS OF
CancerGenetics
The Warburg Effect and Cancer Progression: Glycolytic Reprogramming, Epigenetic Modifications, and Therapeutic Perspectives
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zahra seifi ,1,*
1. Student research committee, Kermanshah university of Medical sciences
- Introduction: Cancer cells require vast amounts of nutrients for continuous growth, leading to reprogrammed energy metabolism, a hallmark of cancer. This altered metabolism causes nutritional deficiencies and waste accumulation, affecting nearby non-tumor cells. During glycolysis, cells break down glucose into pyruvate and ATP. Normal cells can utilize pyruvate in the tricarboxylic acid (TCA) cycle for energy in the presence of oxygen, while tumor cells exhibit high glycolysis levels regardless of oxygen, converting pyruvate to lactate through lactate dehydrogenase (LDH) and limiting mitochondrial metabolism. The Warburg effect, observed by Otto H. Warburg in the early twentieth century, refers to aerobic glycolysis, which helps tumor cells meet their energy and nutritional demands under severe conditions.
- Methods: This review was conducted as a narrative literature analysis focusing on the role of the Warburg effect in cancer metabolism and its implications in cancer progression. Relevant articles were identified by searching PubMed, Scopus, and Web of Science databases using keywords such as “Warburg effect,” “glycolysis,” and “cancer metabolism”. Publications from 2015 to 2025 were included. Priority was given to peer-reviewed articles and recent reviews that provided insights into molecular mechanisms, tumor microenvironment interactions, and potential therapeutic strategies.
- Results: Glycolytic metabolism in cancer cells and their surrounding microenvironment is complex. It has been observed that active glycolysis in cancer is achieved by the upregulation of glycolytic enzymes and transporters, including sodium-glucose linked transporters (SGLTs), hexokinase (HK), phosphofructokinase1 (PFK-1), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), aldolase, enolase, and pyruvate kinase. Increased glycolysis is facilitated by upregulated enzymes primarily regulated by hypoxia-inducible factor 1 (HIF-1) and c-myc. HIF-1 consists of HIF-1α, which senses oxygen levels, and HIF-1β, constitutively expressed. Under normoxia, the von Hippel-Lindau protein (VHL) leads to the degradation of HIF-1α. In low oxygen conditions, HIF-1α is stabilized, forming a heterodimer with HIF-1β that activates target genes in the nucleus. Additionally, oncogene activation (e.g., RAS-induced mTOR) or tumor suppressor inactivation (e.g., p53, PTEN) can increase HIF-1α expression. HIF-1α further promotes glycolytic enzymes like HK2, aldolase, LDHA, and transporters such as MCT4 and GLUT1, enhancing glycolysis. Enhanced glycolysis in cancer cells involves LDH-mediated production of NAD+ from NADH, leading to a reduced NADH: NAD+ ratio that suppresses p53 function. MYC is a commonly amplified oncogene in human cancers. Its protein product, myc, forms a heterodimer with Max to bind E box-containing gene promoters, regulating various genes. Additionally, myc upregulates key glycolytic enzymes and transport proteins like GLUT, LDH, and MCT1, promoting aerobic glycolysis. Elevated glycolytic metabolism is common in cancer cells, providing a selective advantage due to competition for limited nutrients. This increased glycolysis can lead to enhanced glucose consumption, creating a low-glucose environment that hinders immune cell function. Cancer cells also produce significant amounts of lactate, contributing to an acidic tumor microenvironment that promotes local invasion and metastasis while dampening anti-tumor immune responses. Glycolytic metabolism impacts epigenetic modifications in cancer, particularly through the conversion of pyruvate to acetyl-CoA, which leads to histone acetylation. This modification facilitates transcription factor binding, promoting cell growth, and is influenced by cellular signaling and nutritional status. In nutrient deprivation, NAD+ levels rise, promoting deacetylation. Additionally, increased levels of 3-phosphoglycerate (3PG) boost serine synthesis, linking to methylation through the folate and methionine cycles. A novel regulation, histone lactylation, has been identified, indicating that lactate-derived lactylation can also enhance gene transcription. Overall, these processes demonstrate how glycolytic metabolism influences the epigenetic landscape within tumors. Cancer metabolism is a driving force behind cancer development.
- Conclusion: The Warburg effect represents the earliest recognized metabolic characteristic in tumors and continues to evolve, providing new insights for cancer treatment. In this review, we discussed the interplay between Warburg metabolism and cancer progression, emphasizing the crucial role glycolysis plays in reshaping the tumor microenvironment. The modulation of glycolytic enzymes and lactate transporters, such as LDHA and MCT1/4, has demonstrated significant promise in preclinical models. These findings suggest the potential for developing innovative therapeutic strategies targeting cancer progression.
- Keywords: Warburg effect, Glycolysis, Cancer, Epigenetic modification
