The Role of NPM-ALK Signaling in Tumor Cell Metabolism.
dc.contributor.author | McDonnell, Scott Robert Paul | en_US |
dc.date.accessioned | 2013-06-12T14:16:49Z | |
dc.date.available | NO_RESTRICTION | en_US |
dc.date.available | 2013-06-12T14:16:49Z | |
dc.date.issued | 2013 | en_US |
dc.date.submitted | 2013 | en_US |
dc.identifier.uri | https://hdl.handle.net/2027.42/97975 | |
dc.description.abstract | NPM-ALK is a fusion tyrosine kinase that drives oncogenesis in a subset of anaplastic large cell lymphoma. Based on the role of NPM-ALK in cancer initiation and progression, we pursued a mass spectrometry-based phosphoproteomic approach aimed at the unbiased identification of novel mediators of NPM-ALK signaling. The analysis of cell lines under differing NPM-ALK activation conditions revealed a significant number of proteins that regulate cellular metabolism to be affected by NPM-ALK signaling. We therefore, pursued an untargeted metabolomic screen aimed at the identification of specific metabolites and metabolic pathways that are regulated by NPM-ALK. This analysis revealed significant alterations in pathways implicated in the Warburg effect and biomass production, including glycolysis, the pentose phosphate pathway, pyrimidine metabolism, etc. Metabolic flux analysis revealed an NPM-ALK-driven up-regulation of these pathways and down-regulation of energy production. We hypothesized that PKM2 and GSK3β, both identified in the phosphoproteomic study, mediate the metabolic changes. Biochemical studies revealed that NPM-ALK directly phosphorylated PKM2, decreasing its enzymatic activity and driving a metabolic shift away from energy production and toward biomass production. Chemical activation of PKM2 or expression of a mutant PKM2 resulted in a reversal of this metabolic shift and decreased tumorigenesis. The phosphoproteomic analysis identified another candidate mediator of NPM-ALK signaling, GSK3beta. Through the PI3K/AKT pathway, NPM-ALK regulated pS9-GSK3beta, inhibited its activity and provided proteasomal protection for Mcl-1, CDC25A and GYS. This pathway increased proliferation and survival, while increasing glycogen production as a form of metabolic regulation. Studies described in this dissertation globally characterize the ALK driven phosphoproteome and metabolome while providing mechanistic discoveries of two novel NPM-ALK driven pathways. This work provides significant advances to our understanding of oncogenesis and will lead to advances in targeted therapies for ALK driven neoplasms. | en_US |
dc.language.iso | en_US | en_US |
dc.subject | THE ROLE OF NPM-ALK SIGNALING IN TUMOR CELL METABOLISM | en_US |
dc.title | The Role of NPM-ALK Signaling in Tumor Cell Metabolism. | en_US |
dc.type | Thesis | en_US |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Molecular & Cellular Pathology | en_US |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | en_US |
dc.contributor.committeemember | Lim, Megan S. | en_US |
dc.contributor.committeemember | Maillard, Ivan Patrick | en_US |
dc.contributor.committeemember | Cho, Kathleen | en_US |
dc.contributor.committeemember | Donato, Nicholas J. | en_US |
dc.contributor.committeemember | Nikolovska-Coleska, Zaneta | en_US |
dc.contributor.committeemember | Lucas, Peter C. | en_US |
dc.subject.hlbsecondlevel | Pathology | en_US |
dc.subject.hlbtoplevel | Health Sciences | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/97975/1/scottmcd_1.pdf | |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
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