Abstract
The glucose transporter isoform 1 (GLUT1; SLC2A1) is a key rate-limiting factor in the transport of glucose into cancer cells. Enhanced GLUT1 expression and accelerated glycolysis have been found to promote aggressive growth in a range of tumor entities. However, it was unknown whether GLUT1 directly impacts metastasis. Here, we aimed at analyzing the expression and function of GLUT1 in malignant melanoma. Immunohistochemical analysis of 78 primary human melanomas on a tissue micro array showed that GLUT1 expression significantly correlated with the mitotic activity and a poor survival. To determine the functional role of GLUT1 in melanoma, we stably suppressed GLUT1 in the murine melanoma cell line B16 with shRNA. GLUT1 suppressed melanoma cells revealed significantly reduced proliferation, apoptosis resistance, migratory activity and matrix metalloproteinase 2 (MMP2) expression. In a syngeneic murine model of hepatic metastasis, GLUT1-suppressed cells formed significantly less metastases and showed increased apoptosis compared to metastases formed by control cells. Treatment of four different human melanoma cell lines with a pharmacological GLUT1 inhibitor caused a dose-dependent reduction of proliferation, apoptosis resistance, migratory activity and MMP2 expression. Analysis of MAPK signal pathways showed that GLUT1 inhibition significantly decreased JNK activation, which regulates a wide range of targets in the metastatic cascade. In summary, our study provides functional evidence that enhanced GLUT1 expression in melanoma cells favors their metastatic behavior. These findings specify GLUT1 as an attractive therapeutic target and prognostic marker for this highly aggressive tumor.
Highlights
Melanoma is the most aggressive form of skin cancer
Most of the published reports studied epithelial neoplasms, whereas nevi and malignant melanomas arise from melanocytes, which originate from the neural crest, and it is well known that melanocytes and derived cancerous cells have unique metabolic pathways that may interfere with glycolysis
We found that glucose transporter isoform 1 (GLUT1) expression in primary melanomas was an indicator for progression free- and overall survival
Summary
Melanoma is the most aggressive form of skin cancer. Even very thin primary tumors may seed metastases and precipitate rapid death [1, 2]. The worldwide incidence of melanoma is increasing more than in any other neoplastic disease [3]. To date there is no effective therapy for metastatic melanoma and at the molecular level the disease progression is poorly understood [4]. In the 1920s, Otto Warburg made the observation that tumor cells utilize glycolysis instead of mitochondrial oxidative phosphorylation for energy production even under oxygen-rich conditions. The “Warburg effect” has experienced a revival, because it has been shown that aerobic glycolysis governs tumor cell biology [5, 6]
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