Abstract 1134: N-Myc promotes glutamine anaplerosis and aggressive tumor progression through direct GLS2 activation

Abstract

Abstract Elevated glutamine metabolism is an essential feature for malignant transformation. Glutaminase-catalyzed deamidation of glutamine to glutamate is a key step in both glutaminolysis and synthesis of ROS-scavenging glutathione. Two predominant human isozymes of glutaminase, kidney-type GLS1 (also called GLS) and liver-type GLS2, are involved in regulation of glutaminolysis. It has been shown the Myc family member, c-Myc, specifically potentiates elevated expression of GLS1 and promotes the downstream utilization of glutamine carbon in anaplerosis in liver cancer, whereas p53 tumor suppressor specifically activates GLS2 to support cellular defense against oxidative stress, suggesting GLS1 promoted tumorigenesis whereas GLS2 may inhibited it. However, whether cancer cells of different origins use a common or unique signal pathways to regulate glutamine metabolism remains largely unexplored. Using MYCN-amplified neuroblastoma as a model system, we identified GLS2 expression dramatically increased while that of GLS1 substantially decreased in the tumorigenic process of N-Myc transformed neuroblastoma. GLS2 depletion profoundly inhibited glutaminolysis concomitant with a substantial decrease in cell proliferation and viability in vitro and inhibition of tumorigenesis in vivo. Mechanistically, N-Myc, but not p53, selectively activates GLS2 transcription by direct binding to a conserved Myc-binding site within GLS2 promoter. In support of this notion, we found significant elevation of GLS2 expression concomitant with considerable GLS1 down-regulation in primary tumors obtained from MYCN-amplified neuroblastoma patients (invariably with poor prognosis) in comparison with those from MYCN non-amplified patients. In aggregate, these studies suggest that the metabolic regulation of c-Myc induced liver tumors differs from that of N-Myc induced neuroblastoma tumors which is likely to depend on both the genotype and the tissues of origin and have implications regarding the design of selective therapies targeting tumor metabolism. Citation Format: Daibiao Xiao, Ping Ren, Hexiu Su, Ming Yue, Ruijuan Xiu, Lei Gan, Hudan Liu, Guoliang Qing. N-Myc promotes glutamine anaplerosis and aggressive tumor progression through direct GLS2 activation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1134. doi:10.1158/1538-7445.AM2015-1134