Glycolysis is the metabolic pathway that converts glucose into pyruvate, generating ATP and NADH in the process. In cancer cells, glycolysis is often upregulated, even in the presence of oxygen, a phenomenon known as the Warburg effect or aerobic glycolysis. This allows cancer cells to meet their high energy and biosynthetic demands, supporting rapid proliferation and survival.Regulation of glycolysis in cancer cells during aerobic and anaerobic conditions:1. Hypoxia-inducible factor 1 HIF-1 : Under hypoxic low oxygen conditions, HIF-1 is stabilized and activates the transcription of genes involved in glycolysis, such as glucose transporters GLUTs and glycolytic enzymes. In cancer cells, HIF-1 can also be stabilized under normoxic normal oxygen conditions due to genetic alterations or increased reactive oxygen species ROS production, promoting aerobic glycolysis.2. Oncogenes and tumor suppressor genes: Oncogenes like c-Myc and Ras, and loss of tumor suppressor genes like p53, can promote glycolysis in cancer cells. c-Myc upregulates the expression of glycolytic genes and lactate dehydrogenase A LDHA , while Ras activates the PI3K/Akt/mTOR pathway, which in turn increases glucose uptake and glycolysis. Loss of p53 function leads to increased expression of glucose transporters and glycolytic enzymes.3. Enzyme regulation: Key glycolytic enzymes, such as hexokinase 2 HK2 , phosphofructokinase-1 PFK-1 , and pyruvate kinase M2 PKM2 , are often upregulated or allosterically regulated in cancer cells to promote glycolysis. For example, HK2 is overexpressed in many cancers and associates with the outer mitochondrial membrane, providing a direct link between glycolysis and mitochondrial metabolism.Potential therapeutic targets to disrupt glycolysis in cancer cells:1. HIF-1 inhibitors: Targeting HIF-1 can disrupt the upregulation of glycolytic genes and reduce glycolysis in cancer cells. Several HIF-1 inhibitors are under investigation, including small molecules, antisense oligonucleotides, and natural compounds.2. Glycolytic enzyme inhibitors: Inhibiting key glycolytic enzymes can disrupt the glycolytic pathway in cancer cells. Examples include 2-deoxyglucose 2-DG , which inhibits HK2, and 3-bromopyruvate 3-BP , which targets both HK2 and GAPDH. Another approach is to target PKM2, either by activating its pyruvate kinase activity or by inhibiting its non-metabolic functions.3. GLUT inhibitors: Inhibiting glucose transporters can reduce glucose uptake and glycolysis in cancer cells. Several GLUT inhibitors, such as WZB117 and STF-31, are under investigation for their potential anticancer effects.4. Targeting oncogenic and tumor suppressor pathways: Inhibiting oncogenic pathways e.g., PI3K/Akt/mTOR or restoring tumor suppressor function e.g., p53 can indirectly affect glycolysis in cancer cells. Various inhibitors targeting these pathways are in clinical development.5. Lactate dehydrogenase LDH inhibitors: Inhibiting LDH, which catalyzes the conversion of pyruvate to lactate, can disrupt glycolysis and suppress the Warburg effect. Several LDH inhibitors, such as FX11 and GSK2837808A, are under investigation.In summary, glycolysis regulation in cancer cells occurs through various mechanisms, including HIF-1 stabilization, oncogene activation, tumor suppressor loss, and enzyme regulation. Targeting these processes offers potential therapeutic strategies to disrupt glycolysis and inhibit cancer cell growth and survival.