Glucose transporter isoform 1 expression enhances metastasis of malignant melanoma cells.
Glucose transporter isoform 1 expression enhances metastasis of malignant melanoma cells.
复制标题
DOI：
10.18632/oncotarget.4977
复制
发表时间：
2015-10-20
期刊：
影响因子：
--
通讯作者：
Hellerbrand C
中科院分区：
文献类型：
--
作者：
Koch A;Lang SA;Wild PJ;Gantner S;Mahli A;Spanier G;Berneburg M;Müller M;Bosserhoff AK;Hellerbrand C
葡萄糖转运蛋白异构体1 （GLUT1; SLC2A1）是葡萄糖转运到癌细胞的关键限速因子。增强的GLUT1表达和加速的糖酵解已被发现在一系列肿瘤实体中促进侵袭性生长。然而，GLUT1是否直接影响转移尚不清楚。在此，我们旨在分析GLUT1在恶性黑色素瘤中的表达和功能。在组织微阵列上对78例原发性人黑色素瘤的免疫组化分析显示，GLUT1的表达与有丝分裂活性和较差的生存率显著相关。为了确定GLUT1在黑色素瘤中的功能作用，我们用shRNA稳定地抑制了小鼠黑色素瘤细胞系B16中的GLUT1。GLUT1抑制的黑色素瘤细胞增殖、凋亡抵抗、迁移活性和基质金属蛋白酶2 （MMP2）表达显著降低。在同基因小鼠肝转移模型中，与对照细胞形成的转移相比，glut1抑制的细胞形成的转移明显减少，凋亡增加。用药理学GLUT1抑制剂治疗四种不同的人类黑色素瘤细胞系，导致增殖、细胞凋亡抵抗、迁移活性和MMP2表达的剂量依赖性降低。对MAPK信号通路的分析表明，GLUT1抑制显著降低了JNK的激活，JNK在转移级联中调节了广泛的靶点。总之，我们的研究提供了功能证据，表明GLUT1在黑色素瘤细胞中的表达增强有利于其转移行为。这些发现表明GLUT1是这种高度侵袭性肿瘤的一个有吸引力的治疗靶点和预后标志物。
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.