ABSTRACT
Primary effusion lymphoma (PEL) is an aggressive neoplasm caused by Kaposi's sarcoma-associated herpesvirus (KSHV) in immunosuppressed patients and human immunodeficiency virus (HIV)-infected homosexual males. We evaluated the cytotoxic effects of heat shock protein 90 (HSP90) inhibitors on PEL cells. The HSP90 inhibitors geldanamycin (GA), 17(allylamino)-17-demethoxygeldanamycin (17-AAG), and radicicol dramatically inhibited cell proliferation and induced apoptosis of PEL cells through caspase activation. Furthermore, GA induced the stabilization of inhibitor of κB (IκB)α and reduced the phosphorylation of IκBα in PEL cells. HSP90 inhibitors suppressed the transcriptional activity of nuclear factor-kappa B (NF-κB) in PEL cells. It is known that the constitutive activation of NF-κB signaling is essential for the survival of PEL cells and HSP90 contributes to promote activation of NF-κB signaling. The suppression of NF-κB signaling by HSP90 inhibitors may contribute to the induction of apoptosis in PEL cells. In addition, HSP90 activity is required for KSHV replication in KSHV latently infected PEL cells. GA, 17-AAG and radicicol reduced the production of progeny virus from PEL cells at low concentrations, which do not affect PEL cell growth. Our results suggest that HSP90 activity is required for both the survival of PEL cells and viral replication in PEL cells, and that pharmacologic inhibition of HSP90 may be an effective treatment for PEL and KSHV-related diseases.
Subject(s)
Apoptosis/drug effects , Benzoquinones/therapeutic use , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Herpesvirus 8, Human/drug effects , Lactams, Macrocyclic/therapeutic use , Lymphoma, Primary Effusion/drug therapy , Macrolides/therapeutic use , Virus Replication/drug effects , Antibiotics, Antineoplastic/pharmacology , Antibiotics, Antineoplastic/therapeutic use , Benzoquinones/pharmacology , Caspases/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Gene Expression Regulation, Neoplastic , Herpesvirus 8, Human/physiology , Humans , I-kappa B Proteins/metabolism , Lactams, Macrocyclic/pharmacology , Lymphoma, Primary Effusion/metabolism , Lymphoma, Primary Effusion/virology , Macrolides/pharmacology , NF-kappa B/metabolism , Phosphorylation , Sarcoma, Kaposi/complications , Sarcoma, Kaposi/virology , Signal Transduction , Transcription, Genetic/drug effectsABSTRACT
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.
