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 cancer1,2,3,4,5. 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 players6. Although deregulation of metabolism is intimately linked to the proliferative capacity of cells7,8,9,10, and senescent cells are thought to remain metabolically active11, 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 BRAFV600E, an oncogene commonly mutated in melanoma and other cancers. BRAFV600E-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 BRAFV600E-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.
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We thank J.-Y. Song for pathological analysis, M. McMahon for providing BrafCA mice, C. Vogel for sharing cell lines, R. van Amerongen for critical reading of the manuscript, and all members of the Gottlieb and Peeper laboratories for their input. This work was supported by Cancer Research UK, Spanish Government-EU-FEDER (grants SAF2011-25726 and ISCIII-RTICC-RD6/0020/0046) and ICREA-Academia to M.C., Israel Cancer Research Foundation and Israel Science Foundation to T.S., a Vici grant from the Netherlands Organization for Scientific Research (NWO) and a Queen Wilhelmina Award grant from the Dutch Cancer Society (KWF Kankerbestrijding) to D.S.P.
A patent application for combined PDK and MAPK/ERK pathway inhibition in neoplasia has been filed, with J.K. and D.S.P. as inventors.
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Kaplon, J., Zheng, L., Meissl, K. et al. A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence. Nature 498, 109–112 (2013). https://doi.org/10.1038/nature12154
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