MKP-1 Effects on HIF-1alpha and Glycolytic Metabolism in Glioblastoma multiforme

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DESCRIPTION (provided by applicant): Two cardinal features of the tumor cell phenotype are a bioenergetic shift toward glycolytic respiration and apoptotic resistance under high stress conditions. A key regulatory node common to each of these pathways is the hypoxia inducible factor-1¿ (HIF-1¿). Regional hypoxia within the microenvironment of glioblastoma multiforme (GBM) and related somatic mutations converge to stimulate HIF-1¿ activity further enhancing tumor progression. In both immortalized GBM lines and primary resected tumor lysates we find that reduced expression of the MAP kinase phosphatase (MKP-1) correlates with the induction of the HIF-1¿ target mono- carboxylate transporter 4 (MCT4), a lactate transporter critical to homeostasis of glycolytic tumors. By genetically manipulating levels of p53 and MKP-1 in the U87 and U251 tumor lines, we seek to establish a role for MKP-1 and MCT4 in GBM. The effects of MKP-1 on glycolytic metabolism will be assessed using transcriptional analyses to identify effects on HIF-1¿ targets involved in metabolism and survival. Consequently, metabolite analyses will establish the functional role of this signaling pathway. We then establish the relevance of this pathway through the combined Western and immunohistochemical analysis of MKP-1 and MCT4 in clinical GBM samples. In aggregate these studies seek to implicate MKP-1 and MCT4 as clinically relevant markers tumor grade, and to investigate their potential role therapeutic targets for this devastating disease.