Abstract A036: Blocking DNA and RNA synthesis by targeting glutamine metabolism in prostate cancer

Abstract

Abstract Cancer cells greatly increase their uptake of nutrients (glucose, amino acids, and lipids), and metabolize them to provide the necessary building blocks for new cancer cells. It was recently shown that extracellular amino acids make up by far the majority of the carbon sources used by cancer cells for cell division, highlighting amino acid uptake as a viable therapeutic target. In addition, amino acids such as glutamine are critical in providing nitrogen for purine and pyrimidine metabolism. We have previously shown that glutamine uptake is mediated predominantly by ASCT2 in prostate cancer, with ASCT2 knockdown blocking cell growth in vitro and in vivo. Using the TCGA dataset, we have discovered increased expression of downstream glutamine metabolism enzymes in approximately 25% of prostate cancer patients. One of these enzymes, guanine monophosphate synthase (GMPS), is a glutamine amidotransferase involved in de novo purine biosynthesis and is responsible for the last step in the synthesis of the guanine nucleotide. Expression of GMPS correlates with increasing Gleason score in prostate cancer patient samples. Furthermore, patients with high GMPS expression had significantly reduced disease-free survival in the TCGA dataset. Immunofluorescent staining shows that GMPS is localized in both the cytoplasm and nucleus of LNCaP and PC-3 cells—consistent with a secondary role for GMPS in p53 stabilization. Inhibition of GMPS using decoyinine significantly decreased cell growth of both LNCaP and PC-3 cells. Knockdown of GMPS by shRNA significantly decreased cell growth, which could be rescued by addition of extracellular guanosine to the media, suggesting a direct effect on nucleotide synthesis. These results show the importance of downstream glutamine metabolism in prostate cancer, and suggest that GMPS is a potential therapeutic target in “glutamine-addicted” prostate cancers. Citation Format: Qian (Kevin) Wang, Michelle van Geldermalsen, Angel Pang, Blake Zhang, Jeff Holst. Blocking DNA and RNA synthesis by targeting glutamine metabolism in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A036.