Coexpression of glucose transporter 1 and matrix metalloproteinase-2 in human cancers.
BACKGROUND
Cancer cells express higher levels of glucose transporter proteins (Gluts) than do normal cells. Glut-1 overexpression is associated with invasiveness. Because matrix metalloproteinase-2 (MMP-2) is also overexpressed in cancer cells and is associated with invasiveness, we tested the hypothesis that Glut-1 may regulate MMP-2 expression.


METHODS
We transiently transfected Glut-1 complementary DNA (cDNA) or Glut-1 antisense oligonucleotides in the human rhabdomyosarcoma cell line RD and analyzed MMP-2 mRNA expression and cell invasiveness. Empty vector and sense oligonucleotides were used for controls. We analyzed MMP-2 promoter activity in transfectants with a luciferase reporter assay and with p53 and Ets-1 gel mobility shift assays. Eight human cancer cell lines and 80 human cancer specimens were analyzed for coexpression of Glut-1 and MMP-2 by western blot and immunohistochemical analyses, respectively.


RESULTS
Overexpression of Glut-1 in RD cells increased MMP-2 expression 4.3-fold (95% confidence interval [CI] = 3.7-fold to 4.9-fold) and invasiveness 3.2-fold (95% CI = 2.6-fold to 3.8-fold) relative to control transfected cells. Conversely, suppression of Glut-1 expression by antisense oligonucleotides decreased MMP-2 expression by 71.5% (95% CI = 71.1% to 71.9%) and invasiveness by 53.0% (95% CI = 47.5% to 58.5%). Glut-1-mediated MMP-2 expression involved the binding of the transcription factor p53 but not Ets-1. All eight human cancer cell lines coexpressed Glut-1 and MMP-2 by western blotting, and 45 of 80 human tumor tissues coexpressed Glut-1 and MMP-2 by immunohistochemistry.


CONCLUSIONS
MMP-2 expression and cell invasiveness are tightly associated with Glut-1 expression in human cancer cell lines. Because suppression of Glut-1 decreased MMP-2 expression and cancer cell invasion, Glut-1 could be a target for therapy of various cancers that overexpress Glut-1.
Ito
Satoshi
S
Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, University of Tokyo, Japan.
Fukusato
Toshio
T
Nemoto
Takahiro
T
Sekihara
Hisahiko
H
Seyama
Yousuke
Y
Kubota
Shunichiro
S
D015152:Blotting, Northern; D015153:Blotting, Western; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D051272:Glucose Transporter Type 1; D006801:Humans; D007150:Immunohistochemistry; D008156:Luciferases / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis*; D009004:Monosaccharide Transport Proteins / Q000096:biosynthesis*; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000201:enzymology* / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000378:metabolism / Q000494:pharmacology; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D018076:DNA, Complementary; C494041:ETS1 protein, human; D051272:Glucose Transporter Type 1; D009004:Monosaccharide Transport Proteins; D016376:Oligonucleotides, Antisense; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; C495677:SLC2A1 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D008156:Luciferases; D020778:Matrix Metalloproteinase 2; D005947:Glucose