Blockade of Furin Activity and Furin-Induced Tumor Cells Malignant Phenotypes By The Chemically Synthesized Human Furin Prodomain
Processing of cancer-associated precursor proteins such as growth factors by the Proprotein Convertase furin is an important cellular process for acquisition of malignant phenotype and metastatic potential of tumor cells. Furin is inhibited by its own prodomain protein which also plays role in the folding of mature furin. Herein, the complete 83-mer furin prodomain protein was chemically synthesized for the first time by solid phase peptide chemistry and its effects on furin activity and tumor cells malignant phenotypes were evaluated. It inhibited furin activity in a competitive manner with low nanomolar inhibition constant (Ki). Expression of furin prodomain cDNA in tumor cells or cells incubated with the corresponding protein blocked furin-cleavage of proPDGF-A. This was associated with significant reduction in tumor cells proliferation, migration as well as invasion. Interestingly shorter synthetic furin prodomain peptides derived from either its primary or secondary activation site alone weakly inhibited furin and displayed limited effects on tumor cells. This suggests that the combined presence of the above two prodomain segments is crucial for prodomain's potent furin-inhibitory and hence anticancer activities.
No Supplementary Data
No Article Media
Document Type: Research Article
Affiliations: Protein Chemistry Laboratory, Chronic Diseases Program, Ottawa Hospital Research Institute, University of Ottawa, 725 Parkdale Ave, Ottawa, ON K1Y 4E9, Canada.
Publication date: 2010-07-01
More about this publication?
- Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.