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.

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

“…Altered activities of SIRT5 targets, PDC and SDH, are implicated in neoplasia and cancer cell metabolic reprogramming. As previously noted, PDC activity is frequently suppressed in tumor cells, in part via reversible phosphorylation (60,76,80,81,109,115,129,130). It is possible that SIRT5 contributes to metabolic reprogramming in cancer cells, potentially by participating in PDC inhibition.…”

Mitochondria are required for pro‐ageing features of the senescent phenotype

“…ROS have been shown to play important roles in senescence by inducing genomic damage (Parrinello et al , 2003), accelerating telomere shortening (von Zglinicki, 2002) and acting as drivers of signalling networks important for the maintenance of the senescent phenotype (Passos et al , 2010). However, other reports have also highlighted the importance of non‐mitochondrial ROS sources (Takahashi et al , 2006), redox stress (Kaplon et al , 2013) or deficits in antioxidant defence (Blander et al , 2003) in the development of senescence. Therefore, it remains unknown whether mitochondria are truly necessary for senescence.…”

Deoxysphingolipids, a novel biomarker for type 2 diabetes, are cytotoxic for insulin-producing cells

“…In addition, the increased β-galactosidase activity following 1 µM 1-deoxysphinganine treatment or Adp21 infection was accompanied by increased MTT reduction/cell (Fig. S2), suggesting increased mitochondrial dehydrogenase activity, a parameter associated with cellular senescence (18). These data suggest that upregulation of p21 induced by 1 µM 1-deoxysphinganine treatment contributes to the decreased Ins-1 replication by activating a senescence program.…”