Document Detail

DNA damage-induced modulation of GLUT3 expression is mediated through p53-independent extracellular signal-regulated kinase signaling in HeLa cells.
MedLine Citation:
PMID:  20870738     Owner:  NLM     Status:  In-Process    
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.
Masaru Watanabe; Hiroaki Naraba; Tomoko Sakyo; Takayuki Kitagawa
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-09-24
Journal Detail:
Title:  Molecular cancer research : MCR     Volume:  8     ISSN:  1557-3125     ISO Abbreviation:  Mol. Cancer Res.     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-11-25     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101150042     Medline TA:  Mol Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1547-57     Citation Subset:  IM    
Copyright Information:
©2010 AACR.
Department of Cell Biology and Molecular Pathology, Iwate Medical University, School of Pharmacy, 2-1-1 Nishitokuta, Yahaba, Shiwa, Iwate 028-3694, Japan.
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