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Access Type

WSU Access

Date of Award

1-1-2010

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Physiology

First Advisor

Saroj Mathupala

Abstract

Introduction: Malignant glioma display a highly glycolytic phenotype where the tumors flux glucose to lactic acid independent of oxygen concentration ("aerobic glycolysis"). This altered phenotype is facilitated by expression of primarily fetal enzyme isoforms in these malignant tumors. The end-product lactic acid is rapidly expelled from the cytosol by selective monocarboxylate transporters expressed on the plasma membrane. GATA response element islands are present on the promoter of glioma lactate transporter genes, and GATA-1 has been shown to be over-expressed in glioblastoma. Our long-term goal is to inhibit glioma proliferation by indirectly down-regulating GATA-1 to inhibit glycolysis. (Colen et al., 2006; Mathupala et al., 2007; Mathupala et al., 2004)

Methods: We have engineered U87-MG glioblastoma tumor cell lines to either over-express (via viral promoter based vectors) or silence (using siRNA inducible vector systems) GATA-1. Cell proliferation was assessed via both MTT assay and cell cycle analysis. Luciferase based reporter gene analysis was utilized to identify regulation of lactate transporter promoter by GATA-1.

Results: Western blot analysis indicated up- and down-regulation of GATA-1 via the appropriate vector system. Up- or down-regulation of GATA-1 either enhanced or reduced the proliferative rate and the lactate transporter promoter activity.

Conclusions: Regulation of GATA-1 directly impacts glycolytic metabolic flux and proliferation of malignant glioma. Thus, small molecule drugs against GATA-1 may be used as an adjuvant therapy for metabolic targeting of malignant glioma.