Dual treatment with COX-2 inhibitor and sodium arsenite leads to induction of surface Fas Ligand expression and Fas-Ligand-mediated apoptosis in human melanoma cells.
Most human melanomas express Fas receptor on the cell surface, and treatment with exogenous Fas Ligand (FasL) efficiently induces apoptosis of these cells. In contrast, endogenous surface expression of FasL is suppressed in Fas-positive melanomas. We report here the use of a combination of sodium arsenite, an inhibitor of NF-kappaB activation, and NS398, a cyclooxygenase-2 (COX-2) inhibitor, for restoration of the surface FasL expression. We observed a large increase of Fas-mediated apoptosis in Fas-positive melanomas. This was due to induction of FasL surface expression and increased susceptibility to Fas death signaling after arsenite and NS398 treatment. Furthermore, silencing COX-2 expression by specific RNAi also effectively increased surface FasL expression following arsenite treatment. Upregulation of the surface FasL levels was based on an increase in the efficiency of translocation to the cell surface and stabilization of FasL protein on the cell surface, rather than on acceleration of the FasL gene transcription. Data obtained demonstrate that the combination of arsenite with inhibitors of COX-2 may affect the target cancer cells via induction of FasL-mediated death signaling.
Center for Radiological Research, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. vni3@columbia.edu
Vladimir N
VN
Ivanov
Tom K
TK
Hei
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D018053:Arsenites / Q000494:pharmacology*; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053222:Fas Ligand Protein; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D020868:Gene Silencing / Q000502:physiology; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009578:Nitrobenzenes / Q000494:pharmacology*; D034622:RNA Interference / Q000502:physiology; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D017670:Sodium Compounds / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D048069:Tumor Necrosis Factors / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism
D018053:Arsenites; D052246:Cyclooxygenase 2 Inhibitors; D004791:Enzyme Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009578:Nitrobenzenes; D011956:Receptors, Cell Surface; D017670:Sodium Compounds; D013449:Sulfonamides; D048069:Tumor Necrosis Factors; D019014:fas Receptor; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C017947:sodium arsenite; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human