GLUT3 regulates Ras signaling and promotes melanoma metastasis

Summary: Abstract Body: Melanomas express both GLUT1 and the closely related GLUT3 facilitative glucose transporters. In macrophages, GLUT3, but not GLUT1, is essential for M2 macrophage polarization and function, through a transport-independent role in signal transduction. Here, we explored whether GLUT3 might also possess unique signaling functions in melanoma. Knockdown of GLUT1 in melanoma cells inhibited glucose uptake, energy homeostasis, and cell proliferation. GLUT3 knockdown did not affect glucose transport yet showed even more significant effects on cell proliferation. Principal component analyses of RNA sequencing revealed distinct clustering of GLUT1 and GLUT3 knockdown in melanoma cells, and KEGG pathways analyses highlighted alterations in RAS signaling after GLUT3 knockdown. GLUT3 interacted with RAS, regardless of RAS mutation status. Analysis of RAS downstream signaling pathways revealed that p21 activated kinase (PAK) and signal transducer and activator of transcription 3 (STAT3) were decreased, while extracellular signal-regulated kinase (ERK) was increased, by GLUT3 knockdown in melanoma lines. Overexpression of either constitutively active PAK or STAT3 partially rescued GLUT3 knockdown. In human melanoma cell lines, GLUT3 mRNA expression correlated with metastatic potential, and in patient samples, GLUT3, but not GLUT1, expression was higher in metastases when compared with matched primary tumors. GLUT3 overexpressing cell lines showed greater migration and epithelial-mesenchymal transition marker expression in vitro and strikingly higher metastatic potential in vivo. GLUT3 expression was increased in BRAF inhibitor–resistant melanomas, and their RAS-related signaling pathways were dependent on GLUT3 expression. We identify a novel role for GLUT3 in regulating RAS signaling in melanoma and demonstrate its critical role in promoting melanoma metastasis. Dong-Min Yu¹, Rong Yang², Mayuri Vaish¹, Jennifer Gill¹, Richard Wang¹ 1. Dermatology, The University of Texas Southwestern Medical Center, Dallas, TX, United States. 2. Hunan Normal University, Changsha, Hunan, China. Pigmentation, Melanoma, and Melanoma Immune Surveillance