title: Glucose transporter isoform 1 expression enhances metastasis of malignant melanoma cells.
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.
authors: Department of Internal Medicine I, University Hospital Regensburg, Germany.
authors: Andreas
authors: A
authors: Koch
authors: Department of Surgery, University Hospital Regensburg, Germany.
authors: Sven Arke
authors: SA
authors: Lang
authors: Institute of Pathology, University Hospital Zurich, Switzerland.
authors: Peter Johannes
authors: PJ
authors: Wild
authors: Department of Dermatology, University Hospital Regensburg, Germany.
authors: Susanne
authors: S
authors: Gantner
authors: Department of Internal Medicine I, University Hospital Regensburg, Germany.
authors: Abdo
authors: A
authors: Mahli
authors: Department of Cranio-Maxillo-Facial Surgery, University Hospital Regensburg, Germany.
authors: Gerrit
authors: G
authors: Spanier
authors: Department of Dermatology, University Hospital Regensburg, Germany.
authors: Mark
authors: M
authors: Berneburg
authors: Department of Internal Medicine I, University Hospital Regensburg, Germany.
authors: Martina
authors: M
authors: Müller
authors: Institute of Biochemistry, University of Erlangen, Germany.
authors: Anja Katrin
authors: AK
authors: Bosserhoff
authors: Department of Internal Medicine I, University Hospital Regensburg, Germany.
authors: Claus
authors: C
authors: Hellerbrand
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D051272:Glucose Transporter Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D062385:Hydroxybenzoates / Q000494:pharmacology; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D008875:Middle Aged; D034622:RNA Interference; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D013997:Time Factors; D046888:Tissue Array Analysis; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D051272:Glucose Transporter Type 1; D062385:Hydroxybenzoates; C495677:SLC2A1 protein, human; C495678:Slc2a1 protein, mouse; C576807:WZB117; D048031:JNK Mitogen-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse
keywords: GLUT1; JNK; glycolysis; melanoma; metastasis