Primary effusion lymphoma (PEL) is an aggressive neoplasm caused by Kaposi's sarcoma-associated herpesvirus (KSHV). This study provides evidence that proteasomal activity is required for both survival of PEL cells stably harboring the KSHV genome and viral replication of KSHV. We evaluated the cytotoxic effects of proteasome inhibitors on PEL cells. The proteasome inhibitors MG132, lactacystin, and proteasome inhibitor I dramatically inhibited cell proliferation and induced apoptosis of PEL cells through the accumulation of p21 and p27. Furthermore, proteasome inhibitors induced the stabilization of NF-kappa B inhibitory molecule (I kappa B alpha) and suppressed the transcriptional activity of NF-kappa B in PEL cells. The NF-kappa B specific inhibitor BAY11-7082 also induced apoptosis in PEL cells. The constitutive activation of NF-kappa B signaling is essential for the survival and growth of B cell lymphoma cells, including PEL cells. NF-kappa B signaling is upregulated by proteasome-dependent degradation of tau. The suppression of NF-kappa B signaling by proteasome inhibitors may contribute to the induction of apoptosis in PEL cells. In addition, proteasome activity is required for KSHV replication in KSHV latently infected PEL cells. MG132 reduced the production of progeny virus from PEL cells at low concentrations, which do not affect PEL cell growth. These findings suggest that proteasome inhibitors may represent a novel strategy for the treatment of KSHV infection and KSHV-associated lymphomas. (C) 2011 Elsevier Inc. All rights reserved.