Stimulation of human breast carcinoma cell invasiveness and urokinase plasminogen activator activity by glucose deprivation.
Glucose deprivation has been shown to increase the invasive and metastatic potential of tumour cells. In the present study, we determined whether the enhanced tumour cell invasiveness resulting from glucose deprivation is linked to increased activity of enzymes required for extracellular matrix degradation. Results of in vitro invasion assays revealed that the invasiveness of human MDA-MB-231 and MCF-7 breast carcinoma cells and MCF-10A1 normal breast cells was, respectively, 3.9-, 2.9-, and 2.1-fold higher when they were incubated under glucose-deprivation (0.2 mM glucose) than when incubated under physiological blood glucose levels (5 mM). This effect of glucose deprivation on invasion correlated with increased urokinase plasminogen activator (uPA) and plasmin activity. Glucose deprivation did not increase the levels of gelatinase and plasminogen activator inhibitor-1 secretion, or the expression of cell-associated uPA receptor. To determine whether the increased invasiveness resulting from glucose deprivation is causally linked to increased uPA activity, invasion assays were conducted using MDA-MB-231 cells incubated in 0.2 mM or 5 mM glucose in the presence of a neutralising anti-uPA antibody. Results revealed that the anti-uPA antibody significantly inhibited invasion in a dose-dependent manner and to a much greater extent in cells incubated in 0.2 mM glucose than in cells incubated in 5 mM glucose. These results suggest that low glucose levels in malignant cancers increase tumour cell invasiveness by stimulating uPA and plasmin activity.
Department of Anatomy and Cell Biology, Botterell Hall, 9th Floor, Queen's University, Kingston, Ontario, Canada K7L 3N6.
Louiza
L
Belkacemi
Eric
E
Lam
Jason D
JD
Caldwell
D Robert
DR
Siemens
Charles H
CH
Graham
D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D003470:Culture Media / Q000737:chemistry; D005260:Female; D005341:Fibrinolysin / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D003470:Culture Media; D017395:Plasminogen Activator Inhibitor 1; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator; D020782:Matrix Metalloproteinases; D005947:Glucose