A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence
Top Cited Papers
- 19 May 2013
- journal article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 498 (7452), 109-112
- https://doi.org/10.1038/nature12154
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.Keywords
This publication has 35 references indexed in Scilit:
- Abrogation of BRAFV600E-induced senescence by PI3K pathway activation contributes to melanomagenesisGenes & Development, 2012
- Cellular Metabolic Stress: Considering How Cells Respond to Nutrient ExcessMolecular Cell, 2010
- Senescence in tumours: evidence from mice and humansNature Reviews Cancer, 2010
- Healing and Hurting: Molecular Mechanisms, Functions, and Pathologies of Cellular SenescenceMolecular Cell, 2009
- BrafV600E cooperates with Pten loss to induce metastatic melanomaNature Genetics, 2009
- Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activityProceedings of the National Academy of Sciences of the United States of America, 2008
- Brick by brick: metabolism and tumor cell growthCurrent Opinion in Genetics & Development, 2008
- A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumorsGenes & Development, 2007
- Intrinsic tumour suppressionNature, 2004
- Mutations of the BRAF gene in human cancerNature, 2002