The Effects of Heat Shock Protein 90 Inhibitors on Apoptosis and Viral Replication in Primary Effusion Lymphoma Cells

Higashi, Chizuka; Saji, Chiaki; Yamada, Kôji; Kagawa, Hiroyasu; Ohga, Rie; Taira, Takahiro; Fujimuro, Masahiro

doi:10.1248/bpb.35.725

Cited by 20 publications

(20 citation statements)

References 19 publications

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“…Constitutive NF-κB activation is essential for the antiapoptosis and growth of PEL cells (7)(8)(9), consistent with our data, the NF-κB inhibitor BAY11-7082, decreased the viability of PEL cells compared to KSHV-uninfected cells (Fig. 4D), and other NF-κB inhibitors also have PEL-specific cytotoxic effects (10,11). In fact, KSHV targets NF-κB signaling to influence gene expression and apoptosis.…”

Section: Discussionsupporting

confidence: 81%

“…Therefore, DAT-mediated destabilization of TRAF6 induces stabilization of IκBα and the subsequent inhibition of NF-κB signaling, which in turn may result in apoptosis of PEL cells. NF-κB signaling is also required for KSHV replication (10,11). DAT inhibited virus production at low concentrations, such as 0.2 and 1.0 µm (Fig.…”

Section: Discussionmentioning

confidence: 96%

“…Several signaling pathways are activated in PEL cells to maintain malignant potential and enhance cell survival. Especially, the constitutive and/or transient activation of NF-κB signaling is necessary for PEL to achieve the establishment of KSHV infection, survival of infected cells, and viral replication (4,(7)(8)(9)(10)(11). To obtain insight into the machinery by which DAT induces apoptosis of KSHV-infected PEL cells, we analyzed the effect of DAT treatment on NF-κB signaling.…”

Section: Dat Induces Apoptosis Through the Activation Of Caspases In mentioning

confidence: 99%

“…NF-κB signaling is essential for replication of KSHV (10,11). Therefore, we investigated whether DAT suppresses KSHV lytic replication in PEL cells (Fig.…”

Section: Dat Suppresses the Phosphorylation Of Ikkβ Through Downregulmentioning

confidence: 99%

“…These viral proteins and RNA manipulate cellular signaling pathways, including nuclear factor-κB (NF-κB), Akt, Wnt and Erk, to maintain the malignant phenotype and ensure PEL cell survival (4)(5)(6). Especially, NF-κB signaling is constitutively activated in KSHV-infected PEL cells to facilitate antiapoptosis and growth (7)(8)(9)(10)(11). KSHV alternates between lytic replication and latency by RTA expression.…”

Section: Introductionmentioning

confidence: 99%

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Diallyl trisulfide induces apoptosis by suppressing NF-κB signaling through destabilization of TRAF6 in primary effusion lymphoma

Shigemi

Furukawa

Hosokawa

et al. 2015

International Journal of Oncology

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Abstract. The allyl sulfides, including diallyl sulfide (DAS), diallyl disulfide (DAD), and diallyl trisulfide (DAT), contained in garlic and members of the Allium family, have a variety of pharmacological activities. Therefore, allyl sulfides have been evaluated as potential novel chemotherapeutic agents. Here, we found that DAT inhibited nuclear factor-κB (NF-κB) signaling and induced apoptosis in primary effusion lymphoma (PEL), a subtype of non-Hodgkin's B-cell lymphoma caused by Kaposi's sarcoma-associated herpesvirus (KSHV). We examined the cytotoxic effects of DAS, DAD and DAT on PEL cells. DAT significantly reduced the viability of PEL cells compared with uninfected B-lymphoma cells, and induced the apoptosis of PEL cells by activating caspase-9. DAT induced stabilization of IκBα, and suppressed NF-κB transcriptional activity in PEL cells. We examined the mechanism underlying DAT-mediated IκBα stabilization. The results indicated that DAT stabilized IκBα by inhibiting the phosphorylation of IκBα by the IκB kinase (IKK) complex. Furthermore, DAT induced proteasomal degradation of TRAF6, and DAT suppressed IKKβ-phosphorylation through downregulation of TRAF6. It is known that activation of NF-κB is essential for survival of PEL cells. In fact, the NF-κB inhibitor BAY11-7082 induced apoptosis in PEL cells. In addition, DAT suppressed the production of progeny virus from PEL cells. The administration of DAT suppressed the development of PEL cells and ascites in SCID mice xenografted with PEL cells. These findings provide evidence that DAT has antitumor activity against PEL cells in vitro and in vivo, suggesting it to be a novel therapeutic agent for the treatment of PEL. IntroductionPrimary effusion lymphoma (PEL, also termed body-cavitybased lymphoma) is a malignant B-cell lymphoma caused by Kaposi's sarcoma-associated herpesvirus (KSHV, also named HHV-8) in immunosuppressed individuals, such as AIDS patients or those that have undergone organ transplantation (1,2). PEL is a subtype of non-Hodgkin's lymphoma and is characterized by lymphomatous effusions of pleural and abdominal cavities. KSHV is a rhadinovirus of the γ-herpesvirus subfamily and is closely related to herpesvirus Saimiri and Epstein-Barr virus (EBV). KSHV is the causative agent of Kaposi's sarcoma and AIDS-related lymphoproliferative disorders, such as PEL and multicentric Castleman's disease (3). Similar to other herpesviruses, KSHV has two life cycles (latency and lytic replication). The KSHV genome circularizes and forms a double-stranded DNA, the episome, in the nucleus of PEL cells during latent infection. To establish a latent infection, KSHV expresses several viral genes, including latency-associated nuclear antigen (LANA), v-FLIP, v-cyclin, kaposin and microRNAs, in PEL cells. LANA is required for the replication and maintenance of viral DNA, and contributes to KSHV-associated oncogenesis through interaction with cellular molecules, such as p53, Rb and GSK-3. These viral proteins and RNA manipulate cellular signaling pathways, includ...

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 96%

Section: Dat Induces Apoptosis Through the Activation Of Caspases In mentioning

confidence: 99%

“…NF-κB signaling is essential for replication of KSHV (10,11). Therefore, we investigated whether DAT suppresses KSHV lytic replication in PEL cells (Fig.…”

Section: Dat Suppresses the Phosphorylation Of Ikkβ Through Downregulmentioning

confidence: 99%