Abstract 4170: Glucose transporter 2-transported glucosamine inhibits glycolysis in cancer cells through competition with glucose for hexokinase 2

Abstract Anticancer effects of glucosamine, a glucose derivative with a similar structure to glucose, have been discovered, but the molecular mechanisms are not yet fully understood. Since glucosamine and glucose not only have similar structures but also are catalyzed by the same enzyme, hexokinase (HK), in this study, we delved into determining whether the anticancer effect of glucosamine involves the inhibition of glycolysis by competition with glucose. Whole-genome screening analysis showed that many of the gene pathways controlled by glucosamine were directly and indirectly involved in glycolysis. In vitro experiments revealed that as more glucose was added, the anticancer effect of glucosamine decreased. Also, we found that glucosamine was transported into cells mainly through glucose transporter (GLUT) 2 which was responsible for the anticancer effects of glucosamine. In addition, we found that cancer cells with low expression level of HKII show high sensitivity to glucosamine, and a HK inhibitor, 3-bromopyruvate, enhanced the anticancer effect of glucosamine. Under hypoxic conditions, activated hypoxia-inducible factor 1α (HIF-1α) inducing glucose uptake and glycolysis hampered glucosamine-induced cell death, and HIF1A knockdown or HK inhibitors restored glucosamine’s anticancer effects. These findings demonstrate that glucosamine is an efficient glycolysis inhibitor and that GLUT2 and HKII play important roles as biomarkers for determining sensitivity to glucosamine. Moreover, our results suggest that the anticancer effect of glucosamine may be more efficient when administered in combination with other glycolytic agents or inhibitors targeting HIF-1α. Citation Format: Se Yong Park, Ki-Hoon Song, Ju-Hee Kang, Jung Ho Hwang, Seung Hyun Oh. Glucose transporter 2-transported glucosamine inhibits glycolysis in cancer cells through competition with glucose for hexokinase 2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4170.