Serine protease inhibitors interact with IFN-γ through up-regulation of FasR; a novel therapeutic strategy against cancer.

Abstract

Among the many immunomodulatory and anti-tumor activities, IFN-γ up-regulates tumor cell death mediated by Fas receptor (FasR). Our and several other studies have demonstrated the involvement of trypsin-like proteases (TLPs) in the mode of action of IFN-γ. In the present study, we tried to unravel the role of serine proteases in IFN-γ induced Fas-mediated cell death. Our present results show that both tosyl-l-Lysine chloromethylketone (TLCK), a trypsin like protease inhibitor and tosyl-l-phenylalanine chloromethylketone (TPCK) - a chymotrypsin like protease (CLP) inhibitor, sensitize HeLa cells to Fas-mediated cell death. The combined effect of these protease inhibitors with anti-Fas was stronger than additive. In contrast, elastase inhibitor III (EI), which also contains the chloromethyl ketone moiety, was not active. Furthermore, co-addition of TLCK or TPCK with IFN-γ markedly enhanced Fas-induced cell death. IFN-γ led to up-regulation of FasR on its own, which was further enhanced by the co-addition of TLCK or TPCK. This was evident both by increased expression of Fas receptor on cell surface and by elevated Fas mRNA level. This study may provide the basis for the design of a novel combinatory therapeutic strategy that could enhance the eradication of tumors.

• Authors: Natalia Shadrin, Michal Glickman Shapira, Boris Khalfin, Lakshminarasaiah Uppalapati, Abraham H Parola, Ilana Nathan
• Journal: Experimental cell research (Exp Cell Res) Vol. 330 Issue 2 Pg. 233-239 (Jan 15 2015) ISSN: 1090-2422 [Electronic] United States
• PMID: 25449698 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Fas Ligand Protein
• RNA, Messenger
• Serine Proteinase Inhibitors
• fas Receptor
• Tosyllysine Chloromethyl Ketone
• Tosylphenylalanyl Chloromethyl Ketone
• Interferon-gamma
• Serine Endopeptidases

Topics

• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Drug Synergism
• Fas Ligand Protein (metabolism)
• HT29 Cells
• HeLa Cells
• Humans
• Interferon-gamma (pharmacology)
• Neoplasms (drug therapy, pathology)
• RNA, Messenger (biosynthesis)
• Serine Endopeptidases (metabolism)
• Serine Proteinase Inhibitors (pharmacology)
• Tosyllysine Chloromethyl Ketone (pharmacology)
• Tosylphenylalanyl Chloromethyl Ketone (pharmacology)
• Up-Regulation
• fas Receptor (biosynthesis, genetics)