Journal Article

A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence

Chaneton, Barbara, Kaplon, Joanna, Peeper, Daniel S., Cascante, Marta, Gottlieb, Eyal, Meissl, Katrin, Mackay, Gillian, van der Burg, Sjoerd H., Verdegaal, Elizabeth M. E., Zheng, Liang, Shlomi, Tomer, Selivanov, Vitaly A.

2013

Overview

Pyruvate dehydrogenase (PDH) is identified as a crucial mediator of BRAF V600E -induced cellular senescence: PDH is activated by BRAF-mediated suppression of PDK1, enhancing oxidative glucose metabolism, and PDK1 depletion eradicates mutant BRAF melanomas, indicating that this relationship between cell senescence and metabolism might be exploited therapeutically. Cell senescence link to metabolic signalling Oncogene-induced senescence (OIS) is one of the mechanisms that protect humans against cancer, reducing the number of potentially proliferating cells in response to stimulation by tumour suppressors. This study identifies a mechanism for communication between OIS and a mitochondrial signalling axis that balances glycolysis and oxidative phosphorylation. Joanna Kaplon et al . observe a shift from glycolysis to oxidative metabolism of glucose during oncogene-induced cellular senescence. This metabolic shift requires the activation of pyruvate dehydrogenase (PDH) via suppression of PDK1 and induction of PDP2. Inhibition of PDK1 can cause regression of established melanomas in a mouse model. These findings point to PDK1 as a potential target in cancer therapy. 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 1 , 2 , 3 , 4 , 5 . 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 6 . Although deregulation of metabolism is intimately linked to the proliferative capacity of cells 7 , 8 , 9 , 10 , and senescent cells are thought to remain metabolically active 11 , 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/67 / 631/80/509 / Aging / Animal models / Animals / Cell Line / Cellular Senescence - genetics / Citric Acid Cycle / Dehydrogenase / Deregulation / Disease Models, Animal / Enzyme Activation / Glycolysis / Humanities and Social Sciences / Humans / Kinases / letter / Melanoma / Melanoma - drug therapy / Melanoma - enzymology / Melanoma - genetics / Melanoma - pathology / Metabolites / Mice / Mice, Inbred NOD / Mice, SCID / Mitochondria - enzymology / Mitochondria - metabolism / Molecular Targeted Therapy / multidisciplinary / Oncogenes / Oncogenes - genetics / Oxidative Phosphorylation / Physiological aspects / Protein-Serine-Threonine Kinases - antagonists & inhibitors / Protein-Serine-Threonine Kinases - deficiency / Protein-Serine-Threonine Kinases - metabolism / Proteins / Proto-Oncogene Proteins B-raf - genetics / Pyruvate Dehydrogenase (Lipoamide)-Phosphatase - metabolism / Pyruvate dehydrogenase complex / Pyruvate Dehydrogenase Complex - metabolism / Rodents / Science / Signal Transduction / Subpopulations / Tumor suppressor genes