title: A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence.
abstract: In response to tenacious stress signals, such as the unscheduled activation of oncogenes, cells can mobilize tumour suppressor networks to avert the hazard of malignant transformation. A large body of evidence indicates that oncogene-induced senescence (OIS) acts as such a break, withdrawing cells from the proliferative pool almost irreversibly, thus crafting a vital pathophysiological mechanism that protects against cancer. Despite the widespread contribution of OIS to the cessation of tumorigenic expansion in animal models and humans, we have only just begun to define the underlying mechanism and identify key players. Although deregulation of metabolism is intimately linked to the proliferative capacity of cells, and senescent cells are thought to remain metabolically active, little has been investigated in detail about the role of cellular metabolism in OIS. Here we show, by metabolic profiling and functional perturbations, that the mitochondrial gatekeeper pyruvate dehydrogenase (PDH) is a crucial mediator of senescence induced by BRAF(V600E), an oncogene commonly mutated in melanoma and other cancers. BRAF(V600E)-induced senescence was accompanied by simultaneous suppression of the PDH-inhibitory enzyme pyruvate dehydrogenase kinase 1 (PDK1) and induction of the PDH-activating enzyme pyruvate dehydrogenase phosphatase 2 (PDP2). The resulting combined activation of PDH enhanced the use of pyruvate in the tricarboxylic acid cycle, causing increased respiration and redox stress. Abrogation of OIS, a rate-limiting step towards oncogenic transformation, coincided with reversion of these processes. Further supporting a crucial role of PDH in OIS, enforced normalization of either PDK1 or PDP2 expression levels inhibited PDH and abrogated OIS, thereby licensing BRAF(V600E)-driven melanoma development. Finally, depletion of PDK1 eradicated melanoma subpopulations resistant to targeted BRAF inhibition, and caused regression of established melanomas. These results reveal a mechanistic relationship between OIS and a key metabolic signalling axis, which may be exploited therapeutically.
authors.affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Joanna
authors.initials: J
authors.lastname: Kaplon
authors.forename: Liang
authors.initials: L
authors.lastname: Zheng
authors.forename: Katrin
authors.initials: K
authors.lastname: Meissl
authors.forename: Barbara
authors.initials: B
authors.lastname: Chaneton
authors.forename: Vitaly A
authors.initials: VA
authors.lastname: Selivanov
authors.forename: Gillian
authors.initials: G
authors.lastname: Mackay
authors.forename: Sjoerd H
authors.initials: SH
authors.lastname: van der Burg
authors.forename: Elizabeth M E
authors.initials: EM
authors.lastname: Verdegaal
authors.forename: Marta
authors.initials: M
authors.lastname: Cascante
authors.forename: Tomer
authors.initials: T
authors.lastname: Shlomi
authors.forename: Eyal
authors.initials: E
authors.lastname: Gottlieb
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Peeper
mesh_terms: D000818:Animals; D002460:Cell Line; D016922:Cellular Senescence / Q000235:genetics*; D002952:Citric Acid Cycle; D004195:Disease Models, Animal; D004789:Enzyme Activation; D006019:Glycolysis; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008928:Mitochondria / Q000201:enzymology* / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009857:Oncogenes / Q000235:genetics*; D010085:Oxidative Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D011769:Pyruvate Dehydrogenase (Lipoamide)-Phosphatase / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C000631429:PDK1 protein, human; C000631433:Pdk1 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex; C482119:BRAF protein, human; D017346:Protein Serine-Threonine Kinases; D048493:Proto-Oncogene Proteins B-raf; D011769:Pyruvate Dehydrogenase (Lipoamide)-Phosphatase