Abstract A09: The role of asparagine in glutamine-independent proliferation of breast cancer cells

Abstract

Abstract The majority of proliferating cells utilize the carbon backbone of glutamine as a major anaplerotic input into the TCA cycle. In addition, glutamine serves as a donor of reduced nitrogen for the biosynthesis of purine and pyrimidine nucleotides, as well as for a number of non-essential amino acids. Thus, cells rely on external sources of glutamine for biomass accumulation and growth. However, recent data indicate that some cancer cell types – luminal breast cancer lines in particular – are able to proliferate in the absence of exogenous glutamine. Furthermore, luminal breast cancer lines display increased expression of GLUL (glutamine synthetase) and reduced expression of GLS1 (glutaminase), when compared to basal subtype. We sought to identify key metabolic determinants of glutamine-independent proliferation. As our preliminary data indicate, the presence of amino acid asparagine is required for the proliferation of luminal breast cancer cells as well as normal breast epithelial cells in the setting of glutamine deprivation. Both asparagine and glutamine contain amide groups in their respective side chains and are thus structurally similar to each other. However, most normal mammalian tissues – with the exception of the liver and the kidney – are unable to catabolize asparagine, making it essentially metabolically inert for the majority of cell types. Our group has previously shown that asparagine suppresses cell death in cells that depend on glutamine for survival. In this study, we attempt to elucidate the mechanism by which asparagine facilitates the biomass accumulation and proliferation of glutamine-independent cell types. First, we investigate whether luminal breast cancer cells may possess an ability to catabolize asparagine in a manner similar to glutaminolysis and thus use it as an alternative source of reduced nitrogen and carbon in a setting of glutamine deprivation. Second, we explore a potential regulatory metabolic function of asparagine, whereby it may regulate cellular glutamine synthesis and thus enable proliferation in conditions of glutamine deprivation. Citation Format: Natalya N. Pavlova, Craig B. Thompson. The role of asparagine in glutamine-independent proliferation of breast cancer cells. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A09.