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.
See also the human disease model report 'cancer, epithelial, glycolytic tumor model' (FBhh0000959). The Warburg effect may be one of the contributing factors in the development of cachexia. See human disease model reports 'cachexia, IGFBP-related' (FBhh0000535) and 'cachexia, yki-induced ISC tumor model' (FBhh0001115).
[updated Feb. 2020 by FlyBase; FBrf0222196]
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]
Many to one (3 human to 1 Drosophila); multiple lower scoring orthologs in human. The human genes are ESRRG, ESRRB, and ESRRA.
Many to one (3 human to 1 Drosophila); multiple lower scoring orthologs in human. The human genes are ESRRG, ESRRB, and ESRRA.
Many to one (3 human to 1 Drosophila); multiple lower scoring orthologs in human. The human genes are ESRRG, ESRRB, and ESRRA.
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.
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.
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.
