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Induction of apoptosis through extrinsic/intrinsic pathways and suppression of ERK/NF-?B signalling participate in anti-glioblastoma of imipramine.

ABSTRACT: Glioblastomas are the most aggressive type of brain tumour, with poor prognosis even after standard treatment such as surgical resection, temozolomide and radiation therapy. The overexpression of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B) in glioblastomas is recognized as an important treatment target. Thus, an urgent need regarding glioblastomas is the development of a new, suitable agent that may show potential for the inhibition of extracellular signal-regulated kinase (ERK)/NF-?B-mediated glioblastoma progression. Imipramine, a tricyclic antidepressant, has anti-inflammatory actions against inflamed glial cells; additionally, imipramine can induce glioblastoma toxicity via the activation of autophagy. However, whether imipramine can suppress glioblastoma progression via the induction of apoptosis and blockage of ERK/NF-?B signalling remains unclear. The main purpose of this study was to investigate the effects of imipramine on apoptotic signalling and ERK/NF-?B-mediated glioblastoma progression by using cell proliferation (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide [MTT] assay), flow cytometry, Western blotting, and cell invasion/migration assay analysis in vitro. The ERK and NF-?B inhibitory capacity of imipramine is detected by NF-?B reporter gene assay and Western blotting. Additionally, a glioblastoma-bearing animal model was used to validate the therapeutic efficacy and general toxicity of imipramine. Our results demonstrated that imipramine successfully triggered apoptosis through extrinsic/intrinsic pathways and suppressed the invasion/migration ability of glioblastoma cells. Furthermore, imipramine effectively suppressed glioblastoma progression in vivo via the inhibition of the ERK/NF-?B pathway. In summary, imipramine is a potential anti-glioblastoma drug which induces apoptosis and has the capacity to inhibit ERK/NF-?B signalling.

SUBMITTER: Hsu FT

PROVIDER: S-EPMC7171418 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Induction of apoptosis through extrinsic/intrinsic pathways and suppression of ERK/NF-κB signalling participate in anti-glioblastoma of imipramine.

Hsu Fei-Ting FT Chiang I-Tsang IT Wang Wei-Shu WS

Journal of cellular and molecular medicine 20200309 7

Glioblastomas are the most aggressive type of brain tumour, with poor prognosis even after standard treatment such as surgical resection, temozolomide and radiation therapy. The overexpression of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in glioblastomas is recognized as an important treatment target. Thus, an urgent need regarding glioblastomas is the development of a new, suitable agent that may show potential for the inhibition of extracellular signal-regulate ...[more]

PMID: 32149465

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Project description:Interactions between the insect immune system and RNA viruses have been extensively studied in Drosophila, in which RNA interference, NF-κB, and JAK-STAT pathways underlie antiviral immunity. In response to RNA interference, insect viruses have convergently evolved suppressors of this pathway that act by diverse mechanisms to permit viral replication. However, interactions between the insect immune system and DNA viruses have received less attention, primarily because few Drosophila-infecting DNA virus isolates are available. In this study, we used a recently isolated DNA virus of Drosophila melanogaster, Kallithea virus (KV; family Nudiviridae), to probe known antiviral immune responses and virus evasion tactics in the context of DNA virus infection. We found that fly mutants for RNA interference and immune deficiency (Imd), but not Toll, pathways are more susceptible to Kallithea virus infection. We identified the Kallithea virus-encoded protein gp83 as a potent inhibitor of Toll signalling, suggesting that Toll mediates antiviral defense against Kallithea virus infection but that it is suppressed by the virus. We found that Kallithea virus gp83 inhibits Toll signalling through the regulation of NF-κB transcription factors. Furthermore, we found that gp83 of the closely related Drosophila innubila nudivirus (DiNV) suppresses D. melanogaster Toll signalling, suggesting an evolutionarily conserved function of Toll in defense against DNA viruses. Together, these results provide a broad description of known antiviral pathways in the context of DNA virus infection and identify the first Toll pathway inhibitor in a Drosophila virus, extending the known diversity of insect virus-encoded immune inhibitors.IMPORTANCE Coevolution of multicellular organisms and their natural viruses may lead to an intricate relationship in which host survival requires effective immunity and virus survival depends on evasion of such responses. Insect antiviral immunity and reciprocal virus immunosuppression tactics have been well studied in Drosophila melanogaster, primarily during RNA, but not DNA, virus infection. Therefore, we describe interactions between a recently isolated Drosophila DNA virus (Kallithea virus [KV]) and immune processes known to control RNA viruses, such as RNA interference (RNAi) and Imd pathways. We found that KV suppresses the Toll pathway and identified gp83 as a KV-encoded protein that underlies this suppression. This immunosuppressive ability is conserved in another nudivirus, suggesting that the Toll pathway has conserved antiviral activity against DNA nudiviruses, which have evolved suppressors in response. Together, these results indicate that DNA viruses induce and suppress NF-κB responses, and they advance the application of KV as a model to study insect immunity.

Dataset Information

Induction of apoptosis through extrinsic/intrinsic pathways and suppression of ERK/NF-?B signalling participate in anti-glioblastoma of imipramine.

Publications

Induction of apoptosis through extrinsic/intrinsic pathways and suppression of ERK/NF-κB signalling participate in anti-glioblastoma of imipramine.

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