Activation of cancer cell proteases and cytotoxicity by EGF and PDGF growth factors.
The biological effects of EGF and PDGF growth factors on A172 and hEGFr-3T3 cell lines were studied using RBC induced cytolysis and polyacrylamide-gelatin gel electrophoresis assays. The authors report that growth factor-induced cytotoxicity in these cells is mediated by proteolytic enzymes. Treatment of A172 cells with either EGF or PDGF resulted in marked increase of their cytotoxicity (Release Index = 150%). Similarly, RBC induced release index by hEGFr-3T3 cells was elevated to 420% in the presence of 3.4 pM of EGF. However, in A172 cells, PDGF did not have a significant effect on DNA and protein synthesis indicating that stimulation of proteolytic activity is independent of the growth factor signaling pathway. Growth factor induced cytotoxicity was significantly reduced by protease inhibitors in both cell lines. Using EDTA and leupeptin several proteolytic species were identified and localized to cellular membranes as evidenced by polyacrylamide-gelatin electrophoresis assay. These data suggest that growth factors regulate the activation or secretion of proteolytic enzymes in cancer cells and may mediate the invasive and metastatic behavior of these cells.
Department of Medicine, Northport Veterans Administration Medical Center, Stony Brook, New York.
J F
JF
Di Stefano
M
M
Kirchner
K
K
Dagenhardt
N
N
Hagag
D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D010447:Peptide Hydrolases / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D014107:Tosyllysine Chloromethyl Ketone / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000201:enzymology
D007976:Leupeptins; D010982:Platelet-Derived Growth Factor; D014107:Tosyllysine Chloromethyl Ketone; D004815:Epidermal Growth Factor; D000584:Amiloride; D003513:Cycloheximide; D010447:Peptide Hydrolases