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

Abstract

// Arnaldur Hall 1 , 2 , Kathrine Damm Meyle 3 , Marina Krarup Lange 1 , Martin Klima 1 , May Sanderhoff 4 , Christina Dahl 5 , Cecilie Abildgaard 5 , Katrine Thorup 5 , Seyed Moein Moghimi 2 , Per Bo Jensen 4 , Jiri Bartek 1 , Per Guldberg 5 and Claus Christensen 1 1 Genome Integrity Unit, Danish Cancer Society Research Center, Denmark 2 Centre for Pharmaceutical Nanotechnology and Nanotoxicology, University of Copenhagen, Denmark 3 Research Unit for Dietary Studies Institute of Preventive Medicine Bispebjerg and Frederiksberg Hospitals, Denmark 4 Seahorse Bioscience Europa, Copenhagen, Denmark 5 Diet, Genes and Environment Unit, Danish Cancer Society Research Center, Denmark Correspondence: Jiri Bartek, email: // Keywords : Oncogene addiction, melanoma, V600E BRAF, the Warburg effect, glycolysis, oxidative phosphorylation Received : April 4, 2013 Accepted : April 6, 2013 Published : April 8, 2013 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.