Senescence: How a Cell’s World Comes to Stop when the K-ras Moves in

Nature (2013) 498, 109-112
Nature (2013) 498, 109-112

Among the cell’s many mechanisms to stop the aberrant cell proliferation characterized in cancer is the activation of Oncogene-induced senescence (OIS), which stops cells from re-entering the cell cycle or developing into tumors. Over the last few years the role of OIS has been contentiously debated, reaching the current consensus that OIS does occur in vivo in human tumors and that key mutations to cell regulation such as K-ras, B-raf, PTEN, and NF1 can trigger cellular senescence. Observations that senescence occurs in benign, but not advanced, tumors supports the conclusion that senescence suppresses tumor development, requiring further cooperative mutations to deactivate this cellular defense mechanism. While these findings have supported the clinical importance of OIS as a potential mode for tumor treatment, no mechanism has been presented to explain its mode of function. Now, a new study by Kaplon et al. (doi: 10.1038/nature12154) proposes a key to the puzzle of OIS activation, with a conclusion that could have radical therapeutic applications.

By using LC-MS and oxygen consumption rates the authors acquired metabolic profiles of cycling cells and two OIS induced human diploid fibroblast (HDFs) models (BRAFV600E and RASG12V) showing increased TCA isotopomers. These results suggested that OIS cells require increased rates of pyruvate oxidation, a highly regulated step in TCA metabolism. This theory was supported by immunoblotting for pyruvate dehydrogenase (PDH), a key mitochondrial enzyme used in pyruvate oxidation, which demonstrated that OIS cells have phosphorylation induced PDH activity. Further immunoblotting for PDH modifying enzymes revealed the downregulation of the kinase PDK1, which inactivates PDH and induction of kinase PDP2, which activates PDH in OIS cells. By assaying the activity of these enzymes the authors provided both a mechanism for the induction of PDH in benign tumors and an explanation for tumorigenic deactivation of OIS rooted in PDK1 induction. Once the authors observed how these modifying enzymes can drive PDH phosphorylation and promote melanoma growth, they were able to test the efficacy of PDK deactivation by depleting PDK1 in melanoma growths. Indeed, PDK1 depleted melanoma cell lines were unable to produce tumors in immunocompromised mice and had decreased resistance to vemurafenib, a treatment for late-stage melanomas. In providing a new mechanistic understanding of OIS activation and proving its clinical relevance in malignant tumors, Kaplon et al. have provided an elegant answer to a current debate while providing direct targets for therapeutic interventions.

One Reply to “Senescence: How a Cell’s World Comes to Stop when the K-ras Moves in”

  1. The intro provided clear information in what was being discussed and why it was an important discussion. As I read this, I thought about how this could transform research into cancer and if it could move treatment research into a new or expanded direction. The discussion did not make that link so I am not sure if the full article would give me that information or if it would result in the need for other reading to get that information.

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