Abstract 5423: Selective inhibition of glucose transporter 3 (GLUT3) suppresses triple-negative breast cancer cell migration by modulating actin cytoskeleton and cell mechanics

Abstract

Abstract Studies have reported clear clinical observations indicating that obesity and diabetes, which often accompany hyperglycemia, are linked to a poor prognosis across various types of cancer. Specifically, multiple clinical studies involving breast cancer patients have demonstrated that hyperglycemia (>7 mM) is associated with an unfavorable prognosis. Despite the evident correlation between elevated glucose levels and cancer metastasis, the causality remains unclear, and the underlying molecular mechanisms are largely unknown. In both normal and diseased physiology, a broad range of tissue glucose levels has been documented, ranging from normal blood circulation (5.5 mM) to normal tissues (1 - 3 mM) and to tumor tissues (<0.5 mM). Consequently, during the early stages of metastasis, cancer cells undergo a significant increase in extracellular glucose levels. The capacity of cancer cells to deform and exert contractile force, collectively known as cell mechanics, plays a crucial role in various stages of metastasis. In our previous work, we demonstrated that elevated extracellular glucose levels boost glycolysis and activate the RhoA signaling pathway. This leads to heightened cell stiffness and increased contractility in human triple-negative breast cancer (TNBC) cells. Furthermore, the modified cell mechanics are associated with enhanced cell migration and invasion. In this study, we present findings indicating that the inhibition of glucose transporter 3 (GLUT3) significantly diminishes the motility of human TNBC cells, including MDA-MB-231 and its highly metastatic variant, MDA-MB-231/HM cells. Mechanistic investigations reveal that GLUT3 inhibition, facilitated by a well-characterized potent GLUT3-selective inhibitor (G3iA), results in reduced glucose uptake and glycolysis. The diminished glycolysis, induced by GLUT3 inhibition, activates 5' AMP-activated protein kinase (AMPK) and enhances the phosphorylation of Yes-associated protein (YAP). Moreover, GLUT3 inhibition leads to a decrease in non-muscle myosin II activity and induces alterations in F-actin rearrangement by influencing actin-binding proteins such as VASP and cofilin. These changes are associated with a reduction in cell migration. In summary, our results suggest that inhibiting GLUT3 modifies the mechanics of TNBC cells, leading to a decrease in cell motility. Given that GLUT3 is notably elevated in TNBC and is linked to metastatic progression and a poor prognosis in breast cancer patients, our findings underscore the need for further in vivo studies to validate G3iA as a potential anti-metastatic drug in hyperglycemic TNBC animal models. Citation Format: Tae-Hyung Kim, Aadil Qadir Bhat, Cristina V. Iancu, Jun-Yong Choe. Selective inhibition of glucose transporter 3 (GLUT3) suppresses triple-negative breast cancer cell migration by modulating actin cytoskeleton and cell mechanics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5423.