Metabolic control of cell death – MetaDeath
Apoptosis is playing a key role in cancer genesis. Nevertheless, It has been recently shown that apoptosis inhibition was NOT sufficient to allow cell survival and transformation. This indicated that, in condition where apoptosis is blocked, a 'death back-up mechanism' can take place and kill the cell before it gives a cancer. Therefore this lead to the notion that transformed cells and cancer cells resistant to chemotherapy have to be able to simultaneously escape both types of cell death. While caspase-dependent apoptosis has been studied in considerable details, until now, little is known about caspase-independent death (CID) regulation in the context of cancer. We recently were the first to identify that the glycolytic enzyme GAPDH, which is upregulated in numerous cancers, was specifically able to inhibit CID (Ricci* et al, Cell 2007, *co-first). Since we extended this work by demonstrating CID's role in chronic myeloid leu'kemia presenting a resistance to imatinib mesylate treatment (submitted). Our goals are to understand how metabolism can control cell death and also to uncover the mechanisms resulting in CID (using in cellulo and pre-clinical models). ' For that matter, we will: i. Evaluate how glycolysis can control death receptor induced death, We have established that glycolysis was able to regulate death receptor (DR)-induced (mainly TRAIL-induced) apoptosis (submitted). In parallel we confirmed that death receptor ligation was able to induce apoptosis and CID at the same time. The goal of aim one is i) to validate in vivo the use of a glycolytic inhibitor as a combine therapy to treat TRAIL resistant cells, ii) to evaluate GAPDH protective effect against DR-mediated CID. ii. Uncover the molecular mechanisms of CID, The PI3K / AKT pathway, as well as the mammalian target of rapamycin (mTOR) pathway are one of the most commonly altered pathways in human tumors. Our preliminary data showed that GAPDH protection toward CID is depending upon a major PTEN decrease. Therefore we will evaluate the implication of the PI3K / AKT/ mTOR survival pathway in CID regulation and also in GAPDH-induced autohpagy (as we already established that autophagy is induced by GAPDH in order to protect cells from CID). iii. Identify CID's molecular signature, The lack of a precise CID signature represents a main obstacle to understand and to study this specific type of cell death. In fact this 'gap' leaded to a lot of confusion in the field. Our recent GAPDH identification as the first gene able to specifically modulate CID represents a unique advantage that we will use to uncover CID signature. We will therefore investigate, the implication of several known proteases in this phenomenon, and we will extend this work by means of a more general proteomic approach. iv. identification of CID's role in vivo (mice models). As there is no information about the role of CID regulation in general and more specifically in vivo, we decided to investigate this phenomenon in T cell regulation upon development. We choose this model as cell deaths are playing key roles in it. To this end, we generated transgenic mice over-expressing GAPDH under plck promoter. Our preliminary observation indicated that those mice are born alive but develop splenomegaly and enlarged thymus over time. Therefore we will i) characterize precisely this mouse phenotype and ii) analyze the respective contribution of CID and apoptosis during T cell regulation. This will be done by crossing plck-GAPDH mice (CID inhibited) with plck-p35 mice (apoptosis inhibited). It is very likely that CID inhibition and more certainly an inhibition of CID and apoptosis at the same time lead to lymphoproliferative and/or autoimmune syndromes in those mice. In conclusion, our research project will allow a better characterization of new aspects of cell death regulation and their connection to lymphogenesis. Understanding the importance of CID in cancer genesis could, in the long run, lead to the emergence of new therapeutic approaches. The proposed studies are ambitious but we think this ambition is justified by the potential for fundamental discoveries in those under-explored areas.
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