TMET-18. TARGETING AMINO ACID METABOLIC VULNERABILITIES IN GLIOBLASTOMA

Abstract

Abstract Tumor cells have different metabolism from normal cell, which is called as cancer metabolism. In normal cells, asparagine is provided by asparagine synthetase (ASNS) from aspartate. On the other hand, in tumor cells, asparagine is needed to be taken in from outside the cells in addition to synthesized by ASNS within the cells, because of rapid growth of the tumor cells. Glioblastoma is one of the aggressive brain tumors, and temozolomide is frequently used. After glioblastoma cells acquire the resistance to temozolomide, no effective chemotherapy remained. The object of this study is to evaluate whether cancer metabolism, especially asparagine, could be a new target of treatment in primary and recurrent glioblastoma. Temozolomide-sensitive glioblastoma cell lines (U251, and U87), and U251- or U87 derived temozolomide-resistant cells, which were obtained after long treatment of temozolomide to parental cells, were used for the experiments. Genetical inhibition of ASNS using siRNA suppressed the proliferation of temozolomide-sensitive glioblastoma cells, inducing apoptosis. Adding of asparagine in the medium reversed the effect of siRNA targeting ASNS. L-asparaginase, which converts asparagine into aspartate, reduced the colonogenicity of glioblastoma cells. L-asparaginase increased the expression of mRNA of ASNS, and inhibition of ASNS potentiated L-asparaginase-induced anti-tumor effect. For temozolomide-resistant U251- or U87-derived cells, inhibition of ASNS also suppressed the colonogenicity of the cells, and inhibition of ASNS enhanced anti-tumor effect by L-asparaginase. In conclusion, targeting asparagine metabolism will be a therapeutic option for temozolomide-sensitive and temozolomide-resistant glioblastoma.