NF-kappaB inhibition restores sensitivity to Fas-mediated apoptosis in lymphoma cell lines.
Failure to perform the Fas-related apoptosis pathway can account for tumor resistance both to chemotherapeutic agents and to immunological effectors. We studied the role of NK-kappaB in Fas-resistance, employing the Fas-sensitive human T-lymphoma HuT78 cell line and its Fas-resistant variants HuT78B1 and HuT78G9. All these cell lines expressed high levels of constitutively activated NF-kappaB. Pretreatment of cells with NF-kappaB inhibitors (PDTC, MG132, or SN50) strongly enhanced CH11-induced apoptosis in HuT78 and Hut78G9 cells, while only MG132 showed a similar potentiating effect in HuT78B1. The described synergism was significantly inhibited by pretreatment with the anti-Fas-blocking antibody ZB4 or with the pancapsase inhibitor Z-VAD-FMK, but not by capsase-8 or -9 inhibitors. Overall, these data suggest that NF-kappaB inhibition may restore the Fas-pathway in Fas-resistant NF-kappaB-overexpressing tumors.
Meli
Maria
M
Department of Pharmacological Sciences, Università di Palermo, 90127 Palermo, Italy. mmeli@unipa.it
D'Alessandro
Natale
N
Tolomeo
Manlio
M
Rausa
Luciano
L
Notarbartolo
Monica
M
Dusonchet
Luisa
L
D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D006801:Humans; D007976:Leupeptins / Q000633:toxicity*; D016399:Lymphoma, T-Cell; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010455:Peptides / Q000633:toxicity; D011392:Proline / Q000031:analogs & derivatives* / Q000633:toxicity*; D013859:Thiocarbamates / Q000633:toxicity*; D019014:fas Receptor / Q000502:physiology*
D000970:Antineoplastic Agents; D007976:Leupeptins; D016328:NF-kappa B; D010455:Peptides; C118258:SN50 peptide; D013859:Thiocarbamates; D019014:fas Receptor; C066229:prolinedithiocarbamate; D011392:Proline; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde