DNA Damage-Induced Modulation of GLUT3 Expression Is Mediated through p53-Independent Extracellular Signal-Regulated Kinase Signaling in HeLa Cells
DNA Damage-Induced Modulation of GLUT3 Expression Is Mediated through p53-Independent Extracellular Signal-Regulated Kinase Signaling in HeLa Cells
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DOI：
10.1158/1541-7786.mcr-10-0011
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发表时间：
2010-11-01
影响因子：
5.2
通讯作者：
Kitagawa, Takayuki
中科院分区：
文献类型：
--
作者：
Watanabe, Masaru;Naraba, Hiroaki;Kitagawa, Takayuki
与正常细胞相比，许多癌细胞表现出葡萄糖摄取和代谢速率的增加。哺乳动物细胞中的葡萄糖摄取是由葡萄糖转运蛋白（GLUT）家族介导的。在这里，我们报道了dna损伤的抗癌药物，如阿霉素和依托泊苷，抑制了HeLa细胞和致瘤性HeLa细胞杂交中GLUT3的表达，而不是GLUT1的表达。通过实时PCR检测，另一种dna损伤剂喜树碱也明显抑制了GLUT3的表达，通过荧光素酶连锁试验检测，喜树碱降低了启动子的活性。这些药物的抑制作用似乎是独立于p53诱导的，当野生型p53在这些细胞中过量产生时，这一点很明显。相反，通过逆转录pcr和启动子实验发现，丝裂原激活蛋白激酶/细胞外信号调节激酶（MAPK/ERK）激酶（MEK）抑制剂U0126（而不是磷酸肌苷3-激酶抑制剂LY294002）可以阻止药物诱导的抑制。此外，HeLa细胞杂交中GLUT3的过度表达增加了对这些药物的抗性，而通过小干扰RNA耗尽该基因使细胞对药物更敏感，从而降低了葡萄糖消耗。结果表明，dna损伤剂通过激活MEK-ERK通路而不依赖于p53，从而降低癌细胞中GLUT3的表达，导致细胞死亡或凋亡。这一发现可能有助于开发基于glut3依赖性葡萄糖代谢的新化疗药物。Mol - Cancer Res；8 (11);1547 - 57。(c) 2010年aacr。
Many cancer cells exhibit increased rates of uptake and metabolism of glucose compared with normal cells. Glucose uptake in mammalian cells is mediated by the glucose transporter (GLUT) family. Here, we report that DNA-damaging anticancer agents such as Adriamycin and etoposide suppressed the expression of GLUT3, but not GLUT1, in HeLa cells and a tumorigenic HeLa cell hybrid. Suppression of GLUT3 expression determined by the real-time PCR was also evident with another DNA-damaging agent, camptothecin, which reduced the promoter's activity as determined with a luciferase-linked assay. The suppression by these agents seemed to be induced independently of p53, and it was evident when wild-type p53 was overproduced in these cells. In contrast, the mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) kinase (MEK) inhibitor U0126 (but not the phosphoinositide 3-kinase inhibitor LY294002) prevented the drug-induced suppression as determined by reverse transcription-PCR and promoter assays. Furthermore, overexpression of GLUT3 in HeLa cell hybrids increased resistance to these drugs, whereas depletion of the gene by small interfering RNA rendered the cells more sensitive to the drugs, decreasing glucose consumption. The results suggest that DNA-damaging agents reduce GLUT3 expression in cancer cells through activation of the MEK-ERK pathway independently of p53, leading to cell death or apoptosis. The findings may contribute to the development of new chemotherapeutic drugs based on the GLUT3-dependent metabolism of glucose. Mol Cancer Res; 8(11); 1547-57. (C) 2010 AACR.