Targeting of a novel fusion protein containing methioninase to the urokinase receptor to inhibit breast cancer cell migration and proliferation.
It has been shown that methionine depletion inhibits tumor cell growth and reduces tumor cell survival. A novel fusion protein targeted specifically to tumor cells was developed. The fusion protein contained two components: the amino terminal fragment of human urokinase (amino acids 1-49) that binds to the urokinase receptor protein expressed on the surface of invasive cancer cells, and the enzyme L-methioninase (containing 398 amino acids) which depletes methionine and arrests the growth of methionine-dependent tumors. The influence of the fusion protein on the growth and motility of human breast cancer cells was examined using a culture wounding assay. It was determined that MCF-7 breast cancer cells, used in this study, were methionine-dependent and that the fusion protein bound specifically to urokinase receptors of the surface of the cancer cells. Further treatment of the cancer cells with fusion protein over the concentration range 10(-8) to 10(-6) M produced a dose-dependent inhibition of both the migration and proliferation index of MCF-7 cells in the culture wounding assay over a period of 1 to 3 days. The results of this study suggest that this novel fusion protein may serve as a prototype for specific targeting of methioninase and perhaps other cytotoxic agents to cancer cells.
Peron
Karine
K
Bioengineering Center and the School of Chemical Engineering and Materials Science, University of Oklahoma, Norman, Oklahoma 73019, USA.
Jones
Tara N
TN
Gauthier
Sebastien A
SA
Nguyen
Thao-Nguyen T
TN
Zang
Xiao-Ping
XP
Barriere
Magali
M
Prévéraud
Damien
D
Soliman
Charles E
CE
Harrison
Roger G
RG
Pento
J Thomas
JT
D001943:Breast Neoplasms / Q000473:pathology*; D013437:Carbon-Sulfur Lyases / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003470:Culture Media; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006801:Humans; D008715:Methionine / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D011956:Receptors, Cell Surface / Q000187:drug effects* / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*
D003470:Culture Media; C524898:PLAUR protein, human; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D011993:Recombinant Fusion Proteins; D008715:Methionine; D013437:Carbon-Sulfur Lyases; C021558:L-methionine gamma-lyase