Open Close
General Information
Name
cancer, aerobic glycolysis (Warburg effect), larval growth model
FlyBase ID
FBhh0000502
Disease Ontology Term
Parent Disease
OMIM
Overview

A metabolic characteristic of aggressive cancers is a switch from oxidative phosphorylation to aerobic glycolysis, referred to as the Warburg effect. In Drosophila, estrogen-related receptor (ERR) directly induces a transcriptional switch in mid-embryogenesis, establishing a very similar metabolic state, one that supports rapid growth during larval stages by up-regulating the genes that act in biosynthetic pathways associated with aerobic glycolysis (see gene report for ERR). This switch in carbohydrate metabolism is not designed to produce ATP (which is more efficiently accomplished via the mitochondrial OXPHOS cascade), but rather to promotes the synthesis of amino acids, lipids, and nucleotides, thereby supporting cellular proliferation.

Animals that lack functional ERR die during the second larval instar. Mutants are severely metabolically compromised, with a 2-fold decrease in ATP levels relative to control larvae, elevated levels of the circulating sugar trehalose, and decreased triglyceride levels. Genes involved in carbohydrate metabolism are downregulated. Lactate is almost completely absent in mutant animals, consistent with lactate dehydrogenase being one of the most highly downregulated genes. Genetic and physical interactions have been described for Dmel\ERR; see below and in the ERR gene report.

Mutations in the fly lactate dehydrogenase gene (Ldh) and the glycerol-3-phosphate dehydrogenase 1 gene (Gpdh1) have been assessed for their impact upon growth and carbohydrate metabolism during the larval stage. Animals carrying Ldh loss-of-function mutations grow at a normal rate; the inability to produce lactate appears to be compensated for by generating excess glycerol-3-phosphate. Larvae carrying loss-of-function mutations in both Ldh and Gpdh1 exhibit growth defects, lethality and decreased glycolytic flux.

[updated Nov. 2019 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: cancer, aerobic glycolysis (Warburg effect), larval growth model
OMIM report
Human gene(s) implicated
Symptoms and phenotype
Genetics
Cellular phenotype and pathology
Molecular information
See Vander Heiden et al., 2009; pubmed:19460999 and Liberti and Locasale, 2016; pubmed:26778478.
ESRRG, ESRRB and ESSRA encode nuclear receptors closely related to the estrogen receptor; they act as transcriptional regulators. [Gene Cards, ESRRG, ESRRB and ESSRA; 2017.02.27]
External links
Disease synonyms
cancer, Warburg effect, ERR model
cancer, aerobic glycolysis (Warburg effect), ERR model
Ortholog Information
Human gene(s) in FlyBase
    Human gene (HGNC)
    D. melanogaster ortholog (based on DIOPT)
    Comments on ortholog(s)
    Many to one (3 human to 1 Drosophila); multiple lower scoring orthologs in human. The human genes are ESRRG, ESRRB, and ESRRA.
    Human gene (HGNC)
    D. melanogaster ortholog (based on DIOPT)
    Comments on ortholog(s)
    Many to one (3 human to 1 Drosophila); multiple lower scoring orthologs in human. The human genes are ESRRG, ESRRB, and ESRRA.
    Human gene (HGNC)
    D. melanogaster ortholog (based on DIOPT)
    Comments on ortholog(s)
    Many to one (3 human to 1 Drosophila); multiple lower scoring orthologs in human. The human genes are ESRRG, ESRRB, and ESRRA.
    Other mammalian ortholog(s) used
      D. melanogaster Gene Information (3)
      Gene Snapshot
      estrogen-related receptor (ERR) encodes a protein that directly induces a transcriptional switch in mid-embryogenesis, up-regulating the genes that act in biosynthetic pathways associated with aerobic glycolysis. This nuclear receptor establishes the metabolic state that supports growth during larval stages. [Date last reviewed: 2019-03-07]
      Cellular component (GO)
      Gene Groups / Pathways
      Comments on ortholog(s)
      High-scoring ortholog of human ESRRG, ESRRB, and ESRRA (1 Drosophila to 3 human); multiple lower scoring orthologs in human. Dmel\ERR shares 38-42% identity and 50-53% similarity with the human genes.
      Orthologs and Alignments from DRSC
      DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
      Gene Snapshot
      Lactate dehydrogenase (Ldh) encodes a protein involved in myoblast fusion and somatic muscle development. [Date last reviewed: 2019-09-19]
      Molecular function (GO)
      Cellular component (GO)
      Gene Groups / Pathways
      Comments on ortholog(s)
      Moderate- to high-scoring ortholog of human LDHA, LDHB, LDHC, LDHAL6A, and LDHAL6B; multiple genes in both species. Dmel\Ldh shares 60-63% identity and 78-83% similarity with LDHA and LDHB.
      Orthologs and Alignments from DRSC
      DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
      Gene Snapshot
      Glycerol-3-phosphate dehydrogenase 1 (Gpdh1) encodes a glycerol-3-phosphate dehydrogenase that catalyzes the oxidation of glycerol-3-phosphate to dihydroxyacetone phosphate. It is involved in triglyceride metabolism, response to hyperoxia and flight behavior. [Date last reviewed: 2019-09-26]
      Gene Groups / Pathways
      Comments on ortholog(s)
      High-scoring ortholog of human GPD1 and GPD1L; multiple genes in both species. Dmel\Gpdh1 shares 61-66% identity and 75-78% similarity with the human genes.
      Orthologs and Alignments from DRSC
      DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
      Synthetic Gene(s) Used (0)
      Summary of Physical Interactions (124 groups)
      protein-protein
      Interacting group
      Assay
      References
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, anti tag western blot
      pull down, autoradiography, two hybrid
      protein-protein
      Interacting group
      Assay
      References
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      RNA-protein
      Interacting group
      Assay
      References
      electrophoretic mobility shift assay, autoradiography, isothermal titration calorimetry, predetermined participant, anti tag coimmunoprecipitation, quantitative reverse transcription pcr
      protein-protein
      Interacting group
      Assay
      References
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      experimental knowledge based
      two hybrid, experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      Alleles Reported to Model Human Disease (Disease Ontology) (5 alleles)
      Models Based on Experimental Evidence ( 1 )
      Allele
      Disease
      Evidence
      References
      Modifiers Based on Experimental Evidence ( 1 )
      Allele
      Disease
      Interaction
      References
      Models Based on Experimental Evidence ( 0 )
      Allele
      Disease
      Evidence
      References
      Modifiers Based on Experimental Evidence ( 3 )
      Genetic Tools, Stocks and Reagents
      Sources of Stocks
      Contact lab of origin for a reagent not available from a public stock center.
      Bloomington Stock Center Disease Page
      Selected mammalian transgenes
      Allele
      Transgene
      Publicly Available Stocks
      Selected Drosophila transgenes
      Allele
      Transgene
      Publicly Available Stocks
      RNAi constructs available
      Allele
      Transgene
      Publicly Available Stocks
      Selected Drosophila classical alleles
      Allele
      Allele class
      Mutagen
      Publicly Available Stocks
      amorphic allele - molecular evidence
      P-element activity
      amorphic allele - molecular evidence
      P-element activity
      loss of function allele
      CRISPR/Cas9
      loss of function allele
      CRISPR/Cas9
      loss of function allele
      spontaneous
      loss of function allele
      spontaneous
      loss of function allele
      spontaneous
      loss of function allele
      natural population
      loss of function allele
      spontaneous
      loss of function allele
      spontaneous
      loss of function allele
      spontaneous
      loss of function allele
      spontaneous
      loss of function allele
      ethyl methanesulfonate
      amorphic allele - genetic evidence
      ethyl methanesulfonate
      loss of function allele
      natural population
      amorphic allele - genetic evidence
      ethyl methanesulfonate
      loss of function allele
      137Cs gamma ray
      loss of function allele
      natural population
      amorphic allele - genetic evidence
      ethyl methanesulfonate
      amorphic allele - genetic evidence
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      137Cs gamma ray
      loss of function allele
      natural population
      loss of function allele
      P-element activity
      loss of function allele
      natural population
      loss of function allele
      natural population
      amorphic allele - genetic evidence
      ethyl methanesulfonate
      loss of function allele
      natural population
      amorphic allele - genetic evidence
      ethyl methanesulfonate
      loss of function allele
      loss of function allele
      natural population
      loss of function allele
      ethyl methanesulfonate
      amorphic allele - genetic evidence
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      natural population
      References (10)