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

Abstract

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...

Lauric acid and myristic acid from Allium sativum inhibit the growth of Mycobacterium tuberculosis H37Ra: in silico analysis reveals possible binding to protein kinase B

“…The pharmacological activity of garlic and the phytochemicals therein are being studied for the past three decades, of which the organosulphur compounds, especially allicin is one among the most-studied compounds (Mikaili et al 2013). Apart from the antimicrobial activity, the selected sulphur compounds from garlic have found to induce apoptosis by suppressing NF-kB signaling through destabilization of TRAF6 in primary effusion lymphoma (Shigemi et al 2016); attenuates oxidation stress, inflammation and endothelial dysfunction in hypercholesterolemic rabbits (El-Sheakh et al 2016) and protects against ischemic stroke in a rat model (Zhang et al 2015).…”

Tumor necrosis factor receptor‐associated factor 6 contributes to malignant behavior of human cancers through promoting AKT ubiquitination and phosphorylation

“…It has also been reported that the amplification of the TRAF6 locus is a somatic and frequent event in several human cancer types . Research findings showed that TRAF6 is important in the activation of the protein kinase complex IKK, which directly activates NF‐κB and, in turn, inhibits apoptosis . Therefore, TRAF6 is thought to function as a tumor activator by influencing apoptosis in cancer cells.…”

“…2,22 Research findings showed that TRAF6 is important in the activation of the protein kinase complex IKK, which directly activates NF-κB and, in turn, inhibits apoptosis. 23,24 Therefore, TRAF6 is thought to function as a tumor activator by influencing apoptosis in cancer cells. However, our previous study showed that TRAF6 does not simply affect NF-κB signaling and apoptosis in cancer cells under 5 Thus, the precise role of TRAF6 in cancer has not been extensively investigated.…”

Effects of sulfide and polysulfides transmitted by direct or signal transduction‐mediated activation of TRPA1 channels

“…Regulation of the IKK complex by sulfide was only investigated in non‐neuronal tissues. Garlic‐derived DATS promoted apoptosis in primary effusion lymphoma cells by inhibiting IKK activity, preventing proteasome‐driven degradation of IκB‐α and consequently suppressing NF‐κB (Shigemi et al ., ). Similar effect of DADS was detected in carbon tetrachloride‐exposed rat hepatocytes (Lee et al ., ).…”