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Warburg Effect

Written/Edited by Dr. Stefan Pellenz, PhD

Oncogenic alterations of the cellular metabolism were long regarded as a secondary effect of cancer, precipitated by genetic changes. More recently, this perception has changed and the deregulation of cellular energetics is now included in the Hallmarks of Cancer since their second iteration in 2011. This understanding is corroborated by the fact that many cancer driver mutations are also implicated in cellular metabolism and an estimated two thirds of cancers have mutations in glycolytic genes.

The most well-known adaptation of cancer cell metabolism is the Warburg effect, or aerobic glycolysis. It is named after Otto Heinrich Warburg who observed in the 1920s the production of lactic acid in tumor cells under aerobic conditions. The Warburg effect describes the preference of tumors for fermentation of glucose to lactate even in the presence of sufficient amounts of oxygen. Pyruvate, the end product of glycolysis, is reduced to lactate instead of being transported into the mitochondria for oxidative phosphorylation through the citric acid cycle. Lactate is transported out of the cell and contributes to the acidification of the tumor microenvironment (TME).

The catabolic efficiency of aerobic glycolysis is considerably lower than for oxidative phosphorylation: aerobic glycolysis only produces 2 ATP molecules per glucose molecule whereas oxidative phosphorylation yields between 32 and 34 molecules of ATP per molecule of glucose. However, it provides a different selective advantage to cancer cells by providing building blocks – nucleotides, amino acids, and lipids - necessary for the proliferation of rapidly growing cancer cells. Because of the diversion of pyruvate towards lactate, glutamate becomes the main carbon source to replenish metabolic intermediates in the mitochondrial citric acid cycle to cover the cancer cells’ energy needs.

Gain of function mutations in the isocitrate dehydrogenase in the cytosol (IDH1) and in mitochondria (IDH2) lead to reduction of the α-ketoglutarate (α-KG) - one of the citric acid cycle metabolites – to R-2-hydroxyglutarate (2-HG). This oncometabolite inhibits α-KG-dependent dioxygenases by decreasing the concentration of their obligate cofactor α-KG. The class of α-KG-dependent dioxygenases comprises various chromatin-modifying demethylases and methyl transferases. Their inhibition leads to CpG island hypermethylation and affects cell fate. α-KG-dependent dioxygenases also include prolyl hydroxylases, which influence activity of the hypoxia-inducible factor 1 (HIF1), a master regulator of transcription in the adaptive response to hypoxia.

Regulation of transcription factors like HIF1 and Myc and activation of signaling pathways like PI3K/AKT signaling have been shown to contribute to the Warburg phenotype in cancer. Inactivation of tumor suppressors like p53 is also an important mechanism. Under normal conditions, p53 negatively regulates glycolysis and promotes oxidative phosphorylation. However, these mechanisms fail under aerobic glycolysis conditions, thus supporting continuous growth and survival of cancer cells.

Related pathways:


  1. Cairns, Harris, Mak: "Regulation of cancer cell metabolism." in: Nature reviews. Cancer, Vol. 11, Issue 2, pp. 85-95, (2011) (PubMed).
  2. Hanahan, Weinberg: "Hallmarks of cancer: the next generation." in: Cell, Vol. 144, Issue 5, pp. 646-74, (2011) (PubMed).
  3. Yang, Ko, Hensley, Jiang, Wasti, Kim, Sudderth, Calvaruso, Lumata, Mitsche, Rutter, Merritt, DeBerardinis: "Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport." in: Molecular cell, Vol. 56, Issue 3, pp. 414-24, (2014) (PubMed).
  4. Ancey, Contat, Meylan: "Glucose transporters in cancer - from tumor cells to the tumor microenvironment." in: The FEBS journal, Vol. 285, Issue 16, pp. 2926-2943, (2019) (PubMed).
  5. Unterlass, Curtin: "Warburg and Krebs and related effects in cancer." in: Expert reviews in molecular medicine, Vol. 21, pp. e4, (2020) (PubMed).
  6. Barbosa, Martel: "Targeting Glucose Transporters for Breast Cancer Therapy: The Effect of Natural and Synthetic Compounds." in: Cancers, Vol. 12, Issue 1, (2020) (PubMed).
  7. Baksh, Finley: "Metabolic Coordination of Cell Fate by α-Ketoglutarate-Dependent Dioxygenases." in: Trends in cell biology, Vol. 31, Issue 1, pp. 24-36, (2021) (PubMed).
  8. Mirzaei, Hamblin: "Regulation of Glycolysis by Non-coding RNAs in Cancer: Switching on the Warburg Effect." in: Molecular therapy oncolytics, Vol. 19, pp. 218-239, (2020) (PubMed).
  9. Hanahan: "Hallmarks of Cancer: New Dimensions." in: Cancer discovery, Vol. 12, Issue 1, pp. 31-46, (2022) (PubMed).

Transporter Proteins

CTH (Cystathionase (Cystathionine gamma-Lyase)):

SLC1A5 (Solute Carrier Family 1 Member 5):

SLC16A3 (Solute Carrier Family 16 (Monocarboxylic Acid Transporters), Member 3):

SLC2A2 (Solute Carrier Family 2 (Facilitated Glucose Transporter), Member 2):

SLC2A3 (Solute Carrier Family 2 (Facilitated Glucose Transporter), Member 3):

BRP44 (Brain Protein 44):

SLC16A1 (Solute Carrier Family 16, Member 1 (Monocarboxylic Acid Transporter 1)):


PDHA1 (Pyruvate Dehydrogenase (Lipoamide) alpha 1):

PDK4 (Pyruvate Dehydrogenase Kinase, Isozyme 4):

PDK3 (Pyruvate Dehydrogenase Kinase, Isozyme 3):

HK3 (Hexokinase 3 (White Cell)):

PFKL (Phosphofructokinase, Liver):

PFKM (phosphofructokinase, Muscle):

PFKP (phosphofructokinase, Platelet):

PDK2 (Pyruvate Dehydrogenase Kinase, Isozyme 2):

PDK1 (Pyruvate Dehydrogenase Kinase 1):

PDHB (Pyruvate Dehydrogenase beta):

PDHE1-B (Pyruvate Dehydrogenase E1 beta Subunit):

PKM - Pyruvate Kinase, Muscle:

TIGAR (TP53 induced glycolysis regulatory phosphatase):

Amino Acid Metabolism

Lipid Synthesis

Citric Acid Cycle

IDH2 (Isocitrate Dehydrogenase 2 (NADP+), Mitochondrial):

IDH1 (Isocitrate Dehydrogenase 1 (NADP+), Soluble):

ME3 (Malic Enzyme 3, NADP(+)-Dependent, Mitochondrial):

alpha-KG Dependent Dioxygenases

EGLN1 (Egl-9 Family Hypoxia Inducible Factor 1):

MLL2 (Myeloid/lymphoid Or Mixed-Lineage Leukemia 2):

KDM2B (Lysine (K)-Specific Demethylase 2B):

KDM2A (Lysine (K)-Specific Demethylase 2A):

KDM5C (Lysine (K)-Specific Demethylase 5C):

KDM5A (Lysine (K)-Specific Demethylase 5A):

KDM3A (Lysine (K)-Specific Demethylase 3A):

KDM3B (Lysine (K)-Specific Demethylase 3B):

KDM4A (Lysine (K)-Specific Demethylase 4A):

Kdm6b (Lysine (K)-Specific Demethylase 6B):

KDM4C (Lysine (K)-Specific Demethylase 4C):

KDM5D (Lysine (K)-Specific Demethylase 5D):

KDM6A (Lysine (K)-Specific Demethylase 6A):

KDM5B (Lysine (K)-Specific Demethylase 5B):

KDM4B (Lysine (K)-Specific Demethylase 4B):

KDM1B (Lysine (K)-Specific Demethylase 1B):

UTY (Ubiquitously Transcribed Tetratricopeptide Repeat Gene, Y-Linked):

TET2 (Tet Methylcytosine Dioxygenase 2):

TET1 (Tet Methylcytosine Dioxygenase 1):

TET3 (Tet Methylcytosine Dioxygenase 3):

KDM4E (Lysine (K)-Specific Demethylase 4E):

MLL4 (Histone-Lysine N-Methyltransferase MLL4):

KMT2B - Lysine (K)-Specific Methyltransferase 2B:

KMT2A - Lysine (K)-Specific Methyltransferase 2A:


ARNT (Aryl Hydrocarbon Receptor Nuclear Translocator):

ARNT2 (Aryl Hydrocarbon Receptor Nuclear Translocator 2):

EPAS1 (Endothelial PAS Domain Protein 1):

ARNTL (Aryl Hydrocarbon Receptor Nuclear Translocator-Like):

HIF3A (Hypoxia Inducible Factor 3, alpha Subunit):

HIF1A (Hypoxia Inducible Factor 1, alpha Subunit (Basic Helix-Loop-Helix Transcription Factor)):

SCO2 (SCO2 Cytochrome C Oxidase Assembly Protein):

AMPK Signaling

PRKAA1 (Protein Kinase, AMP-Activated, alpha 1 Catalytic Subunit):

PRKAA2 (Protein Kinase, AMP-Activated, alpha 2 Catalytic Subunit):

PRKAB1 (Protein Kinase, AMP-Activated, beta 1 Non-Catalytic Subunit):

PRKAB2 (Protein Kinase, AMP-Activated, beta 2 Non-Catalytic Subunit):

PRKAG2 (Protein Kinase, AMP-Activated, gamma 2 Non-Catalytic Subunit):

PRKAG3 (Protein Kinase, AMP-Activated, gamma 3 Non-Catalytic Subunit):

PRKAG1 (Protein Kinase, AMP-Activated, gamma 1 Non-Catalytic Subunit):

PRKAB1/PRKAB2 (Protein Kinase, AMP-Activated, beta 1/2 Non-Catalytic Subunit):

PI3K/AKT/mTor Signaling

GSK3b - GSK3 beta:

AKT1 (V-Akt Murine Thymoma Viral Oncogene Homolog 1):

RPS6KB1 (Ribosomal Protein S6 Kinase, 70kDa, Polypeptide 1):

PIK3CD (Phosphoinositide-3-Kinase, Catalytic, delta Polypeptide):


DEPTOR (DEP Domain Containing mTOR-Interacting Protein):

GAB2 (GRB2-Associated Binding Protein 2):

INPP5D (Inositol Polyphosphate-5-Phosphatase, 145kDa):

GBL (G protein beta subunit-like):

PTPN11 (Protein tyrosine Phosphatase, Non-Receptor Type 11):

PIK3AP1 (phosphoinositide-3-Kinase Adaptor Protein 1):

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