title: 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.affiliation: Departments of Chemistry, Faculty of Natural Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Natalia
authors.initials: N
authors.lastname: Shadrin
authors.affiliation: Departments of Chemistry, Faculty of Natural Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Michal Glickman
authors.initials: MG
authors.lastname: Shapira
authors.affiliation: Departments of Chemistry, Faculty of Natural Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; New-York University, Shanghai, PR China.
authors.forename: Boris
authors.initials: B
authors.lastname: Khalfin
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Lakshminarasaiah
authors.initials: L
authors.lastname: Uppalapati
authors.affiliation: Departments of Chemistry, Faculty of Natural Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; New-York University, Shanghai, PR China. Electronic address: aparola@bgu.ac.il.
authors.forename: Abraham H
authors.initials: AH
authors.lastname: Parola
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; Hematology Institute, Soroka University Medical Center, Beer-Sheva, Israel. Electronic address: nathan@exchange.bgu.ac.il.
authors.forename: Ilana
authors.initials: I
authors.lastname: Nathan
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D053222:Fas Ligand Protein / Q000378:metabolism; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D012697:Serine Endopeptidases / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D014107:Tosyllysine Chloromethyl Ketone / Q000494:pharmacology; D014108:Tosylphenylalanyl Chloromethyl Ketone / Q000494:pharmacology; D015854:Up-Regulation; D019014:fas Receptor / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D053222:Fas Ligand Protein; D012333:RNA, Messenger; D015842:Serine Proteinase Inhibitors; D019014:fas Receptor; D014107:Tosyllysine Chloromethyl Ketone; D014108:Tosylphenylalanyl Chloromethyl Ketone; D007371:Interferon-gamma; D012697:Serine Endopeptidases
keywords: Cancer; Fas; IFN-γ; Protease inhibitors