Abstract B38: Molecular mechanisms and therapeutic implications of argininosuccinate synthesis 1 regulation in targeted arginine- and glutamine-starvation cancer therapy

Abstract

Abstract Argininosuccinate synthetase 1 (ASS1) is the rate-limiting enzyme that catalyzes the biosynthesis of arginine (Arg). Many malignant human tumors are auxotrophic for Arg because ASS1 is silenced. We previously demonstrated that ASS1 is a sensor of Arg auxotrophic response and a chemosensitivity marker for Arg starvation therapy. Upregulation of ASS1 is the primary mechanism of resistance to Arg starvation therapy using Arg-depleting recombinant protein, pegylated arginine deiminase (ADI-PEG20). We will present in this conference that ASS1 is also a sensor for glutamine (Gln)-deprivation response, and that upregulation of ASS1 expression is associated with resistance to Gln-starvation treatments. Knockdown of ASS1 expression resulted in increased sensitivity to both Arg- and Gln-starvation, whereas increased ASS1 expression by ectopic transfection is associated with resistance to both Arg- and Gln-starvation. The addition of permeable fumarate, a metabolite that bridges the tricarboxylic acid and urea cycles, resulted in downregulation of ASS1 expression and increased sensitivity to both Arg- and Gln-deprivation treatments. Metabolically, ASS1 sits in the middle of several metabolic pathways linking Gln and ASS1 metabolism. This may explain how ASS1 can sense both Gln- and Arg-starvation from opposite directions. Mechanistically, the Gln-deprivation response, like the Arg-auxotrophic response, downregulates HIF-1α resulting in de-repression of ASS1. In the meantime, an activator, c-Myc, is upregulated; and the upregulated c-Myc transcriptionally turns on ASS1 expression. We further also demonstrate that Arg starvation-induced c-Myc activation is regulated by the signaling transduction pasthway involving Gas/Axl → PI3 kinase → Akt → GSK3beta → cMyc. Collectively, our results have revealed the molecular basis of auxotropic responses to Arg- and Gln-deprivation, and provided preclinical implications for improving the treatment efficacy of Arg- and Gln-starvation therapies which have been in several current clinical trials. (Supported by NCI grant R01 CA149260.) Note: This abstract was not presented at the conference. Citation Format: Macus Tien Kuo, Wen-Bin Tsai, Yan Long. Molecular mechanisms and therapeutic implications of argininosuccinate synthesis 1 regulation in targeted arginine- and glutamine-starvation cancer therapy [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B38.