title: FK506 restores sensitivity of thymic lymphomas to calcium-mediated apoptosis and the inducible expression of Fas ligand.
abstract: We have previously described that thymic lymphomas from anti HY-TCR transgenic mice were resistant to TCR-induced (calcium-mediated) apoptosis but sensitive to induction of apoptosis by etoposide. A defect of apoptosis in these cells is located downstream of the nuclear receptor Nur77 induction and upstream from the execution of apoptosis. Furthermore, in contrast to the normal thymocytes, the lymphoma cells do not express the Fas receptor on the cell surface. Here we show that Fas ligand (FasL) induction is also abrogated in thymic lymphomas treated with ionomycin but not with etoposide, which still induced the expression of FasL and Fas receptor as well as apoptosis. It suggested a specific inhibition of the calcium-mediated signaling pathway leading to induction of the FasL expression and apoptosis of lymphomas. Sensitivity to ionomycin-induced apoptosis could be restored by FK506 treatment, which also abolished the abrogation of induction of the FasL expression. Moreover, induction of FasL was always accompanied by increase in expression of Fas receptor. These results indicate that FK506, the agent broadly used as immuno-suppressant, can sensitize resistant tumor cells to induction of apoptosis and it could be considered as a potential agent in the combined therapy of thymic lymphomas. In addition, it appeared that the Fas/FasL system can successfully serve as a molecular target for tumor therapy, even for tumor cells initially lacking expression of Fas.
authors.affiliation: Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, 53-114 Wroclaw, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Kalas
authors.forename: Janusz
authors.initials: J
authors.lastname: Matuszyk
authors.forename: Ewa
authors.initials: E
authors.lastname: Ziolo
authors.forename: Leon
authors.initials: L
authors.lastname: Strzadala
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D065095:Calcineurin Inhibitors; D020013:Calcium Signaling / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D053222:Fas Ligand Protein; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008223:Lymphoma / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D013449:Sulfonamides; D016559:Tacrolimus / Q000494:pharmacology*; D013953:Thymus Neoplasms / Q000473:pathology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D019014:fas Receptor / Q000096:biosynthesis / Q000235:genetics
chemical_list: D065095:Calcineurin Inhibitors; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007476:Ionophores; D007546:Isoquinolines; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D013449:Sulfonamides; D014157:Transcription Factors; D019014:fas Receptor; D015759:Ionomycin; D005047:Etoposide; C043204:N-(2-guanidinoethyl)-5-isoquinolinesulfonamide; D017346:Protein Serine-Threonine Kinases; D016559:Tacrolimus