NF-kappaB inhibition in EBV-transformed lymphoblastoid cell lines

Epstein-Barr virus (EBV) transforms B-lymphocytes into lymphoblastoid cell lines usurping multiple signaling pathways including NF-kappaB activation. To determine whether NF-kappaB activity is essential in the growth and survival of EBV-transformed lymphoblastoid cell lines, a non-degradable IkappaBa mutant was expressed under tetracycline regulation in IB4 cells. NF-kappaB inhibition caused caspase 3 and 8 activation, PARP cleavage, and DNA fragmentation indicative of apoptosis. Mitochondrial membrane potential was diminished without release of cytochrome c or apoptosis initiating factor. z-VAD.FMK, a general caspase inhibitor, failed to block apoptosis, indicating a distinct pathway contributes to cell death. Bfl-1 expression, an anti-apoptotic Bcl-2 family member, is diminished after NF-kappaB inhibition whereas Bcl-2 and Bcl-x/L expression is unaffected. These studies suggest that NF-kappaB itself, or NF-kappaB-regulated genes, will be successful molecular targets for the treatment of EBV-associated diseases.