Abstract 39: UDP-N-acetylglucosamine as a regulator of cancer cell signaling and microenvironment

A common feature to most cancers is their disturbed glucose metabolism: increased glucose and glutamine uptake combined with preference to utilize aerobic glycolysis, a phenomenon called Warburg effect. In addition to providing fast, yet inefficient way to produce energy, Warburg effect increases the availability of glycolysis intermediates that function as starting points of metabolic pathways facilitating the fast cell proliferation. One of the pathways involved is the hexosamine biosynthesis producing UDP-N-acetylglycosamine (UDP-GlcNAc). UDP-GlcNAc is a nucleotide sugar with pivotal functions as a key substrate for the synthesis of glycoconjugates like hyaluronan, and as a metabolic sensor that controls cell functions through O-GlcNAcylation of intracellular proteins. UDP-GlcNAc is linked to cancer through its dependence on glycolysis intermediate availability and by the fact that both hyaluronan and O-GlcNAcylation are closely involved in the development and progression of various cancers. Our hypothesis is that the disturbed sugar metabolism increases the levels of UDP-GlcNAc, which implements its tumorigenic effects through hyaluronan and O-GlcNAcylation, and that these changes manifest themselves also in clinical data. In order to test our hypothesis we collected 33 biopsy samples from breast cancer patients, and 13 healthy control samples. Clinical data and immunohistochemical samples are available from the operated patients. From these samples we have analyzed UDP-sugar content with HPLC, hyaluronan levels with ELISA-like method and by immunohistochemistry, and measured mRNA expression of key enzymes with quantitative RT-PCR. Our results show for the first time that UDP-sugars levels are indeed elevated in breast cancer patients. The level of UDP-GlcNAc shows a 12-times increase, while other UDP-sugars were 4 to 6 times higher. To investigate the cause of differential increment of UDP-GlcNAc and other UDP-sugars, we measured the mRNA levels of genes regulating the synthesis of UDP-GlcNAc. Cancer patients had increased expression of GFAT2 while others (GFAT1, GNPDA1 and 2) remained unchanged. In accordance to our hypothesis, the increased levels of UDP-GlcNAc correlated with changes in the mRNA expression of enzymes involved in both hyaluronan synthesis and O-GlcNAcylation of proteins. Our results show that the increased glucose uptake associated to aerobic glycolysis dramatically increases UDP-sugars in breast cancer, promoting malignant growth by increased hyaluronan synthesis and O-GlcNAc signaling. Citation Format: Sanna Oikari, Satu Tiainen, Tiia Kettunen, Amro Masarwah, Ritva Vanninen, Markku Tammi, Paivi Auvinen. UDP-N-acetylglucosamine as a regulator of cancer cell signaling and microenvironment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 39.