title: Dysfunctional oxidative phosphorylation makes malignant melanoma cells addicted to glycolysis driven by the (V600E)BRAF oncogene.
abstract: Oncogene addiction describes how cancer cells exhibit dependence on single oncogenes to escape apoptosis and senescence. While oncogene addiction constitutes the basis for new cancer treatment strategies targeting individual kinases and pathways activated by oncogenic mutations, the biochemical basis for this addiction is largely unknown. Here we provide evidence for a metabolic rationale behind the addiction to (V600E)BRAF in two malignant melanoma cell lines. Both cell lines display a striking addiction to glycolysis due to underlying dysfunction of oxidative phosphorylation (OXPHOS). Notably, even minor reductions in glycolytic activity lead to increased OXPHOS activity (reversed Warburg effect), however the mitochondria are unable to sustain ATP production. We show that (V600E)BRAF upholds the activity of glycolysis and therefore the addiction to glycolysis de facto becomes an addiction to (V600E)BRAF. Finally, the senescence response associated with inhibition of (V600E)BRAF is rescued by overexpression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), providing direct evidence that oncogene addiction rests on a metabolic foundation.
authors.affiliation: Genome Integrity Unit, Danish Cancer Society Research Center, Denmark.
authors.forename: Arnaldur
authors.initials: A
authors.lastname: Hall
authors.forename: Kathrine Damm
authors.initials: KD
authors.lastname: Meyle
authors.forename: Marina Krarup
authors.initials: MK
authors.lastname: Lange
authors.forename: Martin
authors.initials: M
authors.lastname: Klima
authors.forename: May
authors.initials: M
authors.lastname: Sanderhoff
authors.forename: Christina
authors.initials: C
authors.lastname: Dahl
authors.forename: Cecilie
authors.initials: C
authors.lastname: Abildgaard
authors.forename: Katrine
authors.initials: K
authors.lastname: Thorup
authors.forename: Seyed Moein
authors.initials: SM
authors.lastname: Moghimi
authors.forename: Per Bo
authors.initials: PB
authors.lastname: Jensen
authors.forename: Jiri
authors.initials: J
authors.lastname: Bartek
authors.forename: Per
authors.initials: P
authors.lastname: Guldberg
authors.forename: Claus
authors.initials: C
authors.lastname: Christensen
mesh_terms: D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006019:Glycolysis / Q000235:genetics*; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009857:Oncogenes; D010085:Oxidative Phosphorylation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf