The Role of NPM-ALK Signaling in Tumor Cell Metabolism.

THE ROLE OF NPM-ALK SIGNALING IN TUMOR CELL METABOLISM;Pathology;Health Sciences;Molecular & Cellular Pathology

McDonnell, Scott Robert PaulLucas, Peter C. ;

University of Michigan

关键词: THE ROLE OF NPM-ALK SIGNALING IN TUMOR CELL METABOLISM;    Pathology;    Health Sciences;    Molecular & Cellular Pathology;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/97975/scottmcd_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

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.