637 Non-redundant roles for GLUT1 and GLUT3 in melanoma and primary melanocytes

Abstract

The GLUT1 transporter mediates glucose uptake in most tissues and is upregulated in both inflammatory and malignant skin diseases. Most melanomas overexpress both GLUT1 and GLUT3, but it is unclear whether the closely related transporters are functionally redundant. Consistent with its function in keratinocytes, GLUT1 knockdown in melanoma cells (UACC-62 and Mel-juso) inhibited glucose uptake and cell proliferation. Notably, GLUT3 knockdown did not impair glucose transport yet showed even more dramatic effects on cell proliferation and morphology. Fractionation revealed the preferential localization of GLUT1 to the plasma membrane while GLUT3 preferentially localized to endosomes. RNA-sequencing, Western blotting, and immunofluorescence revealed an essential role for GLUT3 in signal transducer and activator of transcription 3 (STAT3) activation, which has been implicated in melanoma growth and metastasis. Deletion of GLUT1 or GLUT3 in primary mouse melanocytes through Tyrosinase-cre expression confirmed a critical role for GLUT3 in STAT3 activation and non-redundant roles for GLUT1 and GLUT3 in pigmentation and melanocyte proliferation ex vivo. These studies identify unique functions for GLUT1 and GLUT3 in melanoma and melanocytes and highlight the GLUT3-STAT3 signaling axis as a potential therapeutic target in melanoma.