Dysfunctional oxidative phosphorylation makes malignant melanoma cells addicted to glycolysis driven by the V600EBRAF oncogene

Arnaldur Hall, Kathrine Damm Meyle, Marina Krarup Lange, Martin Klima, May Sanderhoff, Christina Dahl, Cecilie Abildgaard, Katrine Thorup, Seyed Moein Moghimi, Per Bo Jensen, Jiri Bartek, Per Guldberg, Claus Christensen

Research output: Contribution to journalArticle

111 Scopus citations

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 V600EBRAF 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 V600EBRAF upholds the activity of glycolysis and therefore the addiction to glycolysis de facto becomes an addiction to V600EBRAF. Finally, the senescence response associated with inhibition of V600EBRAF is rescued by overexpression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), providing direct evidence that oncogene addiction rests on a metabolic foundation.

Original languageEnglish (US)
Pages (from-to)584-599
Number of pages16
JournalOncotarget
Volume4
Issue number4
DOIs
StatePublished - Apr 2013

Keywords

  • BRAF
  • Glycolysis Oxidative phosphorylation
  • Melanoma
  • Oncogene addiction
  • The Warburg effect

ASJC Scopus subject areas

  • Oncology

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