title: Proteasome inhibitors induce apoptosis and reduce viral replication in primary effusion lymphoma cells.
abstract: 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-κB inhibitory molecule (IκBα) and suppressed the transcriptional activity of NF-κB in PEL cells. The NF-κB specific inhibitor BAY11-7082 also induced apoptosis in PEL cells. The constitutive activation of NF-κB signaling is essential for the survival and growth of B cell lymphoma cells, including PEL cells. NF-κB signaling is upregulated by proteasome-dependent degradation of IκBα. The suppression of NF-κB 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.
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Saji
authors.forename: Chizuka
authors.initials: C
authors.lastname: Higashi
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Niinaka
authors.forename: Koji
authors.initials: K
authors.lastname: Yamada
authors.forename: Kohji
authors.initials: K
authors.lastname: Noguchi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fujimuro
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D019288:Herpesvirus 8, Human / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D054685:Lymphoma, Primary Effusion / Q000821:virology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009570:Nitriles / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D061988:Proteasome Inhibitors; D013450:Sulfones / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects*
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000970:Antineoplastic Agents; D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D016328:NF-kappa B; D009570:Nitriles; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D013450:Sulfones; C090535:benzyloxycarbonyl-isoleucyl-glutamyl(O-tert-butyl)-alanyl-leucinal; C067713:lactacystin; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D000111:Acetylcysteine