PO19TARGETING ASCT2 BLOCKS GROWTH AND MIGRATION IN A MEDULLOBLASTOMA CELL LINE

Abstract

INTRODUCTION: Medulloblastoma is the most common malignant paediatric brain tumour. Current treatments include surgery and radio/chemotherapy, which are associated with significant side effects, such as neurological, intellectual and physical disabilities. Metabolic adaptation has emerged as a hallmark of cancer and as a promising therapeutic target. Rapidly proliferating cancer cells adapt their metabolism by increasing nutrient uptake and by reorganising metabolic flux to support cell growth, promoting macromolecule synthesis and ATP production. Glutamine is a conditionally essential amino acid in cancer cells, being utilized as a carbon and nitrogen source for macromolecule production as well as for anaplerotic reactions fuelling the tricarboxylic acid cycle. METHOD: In this study, we used the DAOY medulloblastoma cell line. Amino acid starvation reduced cell proliferation but only glutamine starvation induced apoptosis. DAOY cells express high levels of ASCT2. Chemical inhibition (GPNA) or shRNA knockdown of ASCT2 in DAOY cells reduced cell growth and migration in the scratch assay. RESULTS: We demonstrate that the glutamine transporter ASCT2 is highly expressed in the DAOY medulloblastoma cell line. We show that chemical or shRNA-mediated inhibition of ASCT2 in vitro significantly inhibits cell growth, induce apoptosis and inhibit cell migration. CONCLUSION: Glutamine contributes to essentially every core metabolic task of proliferating tumour cells. ASCT2-mediated glutamine uptake is essential for multiple pathways regulating cell growth and cell migration in a medulloblastoma cell line, and it could therefore be a putative therapeutic target for medulloblastoma.