D-Allose Inhibits Cancer Cell Growth by Reducing GLUT1 Expression
D-Allose Inhibits Cancer Cell Growth by Reducing GLUT1 Expression
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DOI：
10.1620/tjem.238.131
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发表时间：
2016-02-01
影响因子：
2.2
通讯作者：
Yamaguchi, Fuminori
中科院分区：
文献类型：
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作者：
Noguchi, Chisato;Kamitori, Kazuyo;Yamaguchi, Fuminori
葡萄糖是哺乳动物细胞的主要能量来源，通过细胞特异性表达的多种葡萄糖转运蛋白(GLUT)被转运到细胞内。特别是，癌细胞需要大量的葡萄糖作为其生长失调的能量来源，从而过度表达谷氨酸。D-异丙糖是D-葡萄糖的C-3异构体，是自然界中少量存在的稀有糖类之一。我们已经证明，D-Allse诱导编码硫氧还蛋白相互作用蛋白(TXNIP)的肿瘤抑制基因，并通过阻止G1期细胞周期来抑制肿瘤细胞的生长。也有报道称，包括GLUT1在内的谷氨酸在许多癌细胞中过度表达，这可能有助于更大程度的葡萄糖利用。由于D-Allse通过上调TXNIP的表达来抑制癌细胞的生长，我们的研究重点在于D-Allose是否通过TXNIP的表达下调GLUT1的表达，从而抑制癌细胞的生长。Western印迹和实时荧光定量聚合酶链式反应分析表明，D-Allose可剂量依赖性地诱导肝细胞癌(HH-7)、高加索人乳腺癌(MDA-MB-231)和神经母细胞瘤(SH-SY5Y)细胞株TXNIP的表达，抑制GLUT1的表达。在这些细胞系中，D-异体硒处理抑制了细胞的生长。重要的是，通过2-脱氧D-葡萄糖的摄取来衡量，D-异体治疗降低了葡萄糖摄取。此外，报告分析表明，D-异丙糖通过存在于被测试启动子区域的低氧反应元件降低了荧光素酶的表达。这些结果表明，D-异丙糖可能通过降低GLUT1的表达和葡萄糖摄取而抑制肿瘤的生长。
Glucose is a major energy source for mammalian cells and is transported into cells via cell-specific expression of various glucose transporters (GLUTs). Especially, cancer cells require massive amounts of glucose as an energy source for their dysregulated growth and thus over-express GLUTs. D-allose, a C-3 epimer of D-glucose, is one of rare sugars that exist in small quantities in nature. We have shown that D-allose induces the tumor suppressor gene coding for thioredoxin interacting protein (TXNIP) and inhibits cancer cell growth by G1 cell cycle arrest. It has also been reported that GLUTs including GLUT1 are over expressed in many cancer cell lines, which may contribute to larger glucose utilization. Since D-allose suppresses the growth of cancer cells through the upregulation of TXNIP expression, our present study focused on whether D-allose down-regulates GLUT1 expression via TXNIP expression and thus suppresses cancer cell growth. Western blot and real-time PCR analyses revealed that D-allose significantly induced TXNIP expression and inhibited GLUT1 expression in a dose-dependent manner in three human cancer cell lines: hepatocellular carcinoma (HuH-7), Caucasian breast adenocarcinoma (MDA-MB-231), and neuroblastoma (SH-SY5Y). In these cell lines, D-allose treatment inhibited cell growth. Importantly, D-allose treatment decreased glucose uptake, as measured by the uptake of 2-deoxy D-glucose. Moreover, the reporter assays showed that D-allose decreased the expression of luciferase through the hypoxia response element present in the tested promoter region. These results suggest that D-allose may cause the inhibition of cancer growth by reducing both GLUT1 expression and glucose uptake.