Silencing Daxx increases the anti-tumor activity of a TRAIL/shRNA Bcl-xL-expressing oncolytic adenovirus through enhanced viral replication and cellular arrest

Kang, Su-Jin; Kang, Dukjin; Islam, S. M. Bakhtiar Ul; Je, Suyeon; Kim, Joo Hang; Song, Jae J.

doi:10.1016/j.cellsig.2015.02.028

Cited by 8 publications

(7 citation statements)

References 32 publications

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“…Adenoviral replication is effectively maintained only when the adenoviral E1B55K protein binds to Daxx and induces its proteasome-dependent degradation 9 . Previously, we showed that Daxx downregulation enhanced adenoviral replication 11 . In this study, we examined cellular Daxx levels in various human and mouse cancer cell lines.…”

Section: Resultsmentioning

confidence: 93%

“…1a). Therefore, we speculated that low adenoviral replication in mouse cells is caused by increased cellular levels of Daxx, which represses adenoviral replication 11,12 . We then examined adenoviral infectivity in mouse and human cancer cells.…”

Section: Resultsmentioning

confidence: 99%

“…Daxx is also a CD95-binding protein that activates c-Jun NH2-terminal kinase (JNK) via directly binding to apoptotic signal-regulating kinase 1 (ASK1) 4,5 . Studies have also implicated Daxx in viral replication 6–11 . We previously observed that silencing of the Daxx gene increased oncolytic adenoviral replication 11 , which is consistent with the fact that effective adenoviral replication is maintained only when the adenoviral protein E1B55K binds to Daxx and triggers its proteasome-dependent degradation 9,12 .…”

Section: Introductionmentioning

confidence: 99%

“…Studies have also implicated Daxx in viral replication 6–11 . We previously observed that silencing of the Daxx gene increased oncolytic adenoviral replication 11 , which is consistent with the fact that effective adenoviral replication is maintained only when the adenoviral protein E1B55K binds to Daxx and triggers its proteasome-dependent degradation 9,12 . Daxx was shown to repress adenoviral replication by binding to α thalassemia/mental retardation syndrome X-linked (ATRX), and replication was restored via mutations that abolished the interaction of Daxx with ATRX 10 .…”

Section: Introductionmentioning

confidence: 99%

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High levels of Daxx due to low cellular levels of HSP25 in murine cancer cells result in inefficient adenovirus replication

et al. 2019

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When the adenoviral protein E1B55K binds death domain-associated protein (Daxx), the proteasome-dependent degradation of Daxx is initiated, and adenoviral replication is effectively maintained. Here, we show that the cellular levels of Daxx differ between human and mouse cancer cell lines. Specifically, we observed higher cellular Daxx levels and the diminished replication of oncolytic adenovirus in mouse cancer cell lines, suggesting that cellular Daxx levels limit the replication of oncolytic adenoviruses that lack E1B55K in murine cells. Indeed, the replication of oncolytic adenoviruses that lack E1B55K was significantly increased following infection with oncolytic adenovirus expressing Daxx-specific shRNA. Cellular Daxx levels were decreased in mouse cells expressing heat shock protein 25 (HSP25; homolog of human HSP27) following heat shock or stable transfection with HSP25-bearing plasmids. Furthermore, Daxx expression in murine cell lines was primarily regulated at the transcriptional level via HSP25-mediated inhibition of the nuclear translocation of the signal transducer and activator of transcription 3 (stat3) protein, which typically upregulates Daxx transcription. Conversely, human HSP27 enhanced stat3 activity to increase Daxx transcription. Interestingly, human Daxx, but not mouse Daxx, was degraded as normal by ubiquitin-dependent lysosomal degradation; however, HSP27 downregulation induced the ubiquitin-independent proteasomal degradation of Daxx.

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Section: Resultsmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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High levels of Daxx due to low cellular levels of HSP25 in murine cancer cells result in inefficient adenovirus replication

et al. 2019

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“…Another advantage of these adenoviral vectors is that they can be double armed with any gene beside the one coding TRAIL to potentiate the tumoural cytotoxicity of the cancer targeted gene virotherapy (CTGVT) or to overcome TRAIL resistance. Reconstruction and recombination of two different adenoviral vectors one carrying shRNA and the other coding TRAIL in E.coli cells resulted in single double armed vector expressing shRNA beside TRAIL [ 68 – 69 ]. These short hairpin RNA that can interfere with cancer cells RNA can be used to silence the expression of anti-apoptotic proteins like the IAP family member survivin [ 68 ], the nuclear protein Daxx [ 69 ], or the β-galactoside binding protein galectin-1 [ 70 ] and thereby augment the cytotoxic effect of TRAIL in cancer cells.…”

Section: Trail Gene Delivery Systemmentioning

confidence: 99%

Role of nanotechnology and gene delivery systems in TRAIL based therapies

Naoum¹,

Tawadros²,

Farooqı³

et al. 2016

ecancer

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Since its identification as a member of the tumour necrosis factor (TNF) family, TRAIL (TNF-related apoptosis-inducing ligand) has emerged as a new avenue in apoptosis-inducing cancer therapies. Its ability to circumvent the chemoresistance of conventional therapeutics and to interact with cancer stem cells (CSCs) self-renewal pathways, amplified its potential as a cancer apoptotic agent. Many recombinant preparations of this death ligand and monoclonal antibodies targeting its death receptors have been tested in monotherapy and combinational clinical trials. Gene therapy is a new approach for cancer treatment which implies viral or non-viral functional transgene induction of apoptosis in cancer cells or repair of the underlying genetic abnormality on a molecular level. The role of this approach in overcoming the traditional barriers of radiation and chemotherapeutics systemic toxicity, risk of recurrence, and metastasis made it a promising platform for cancer treatment. The recent first Food Drug Administration (FDA) approved oncolytic herpes virus for melanoma treatment brings forth the potency of the cancer gene therapy approach in the future. Many gene delivery systems have been studied for intratumoural TRAIL gene delivery alone or in combination with chemotherapeutic agents to produce synergistic cancer cytotoxicity. However, there still remain many obstacles to be conquered for this different gene delivery systems. Nanomedicine on the other hand offers a new frontier for clinical trials and biomedical research. The FDA approved nanodrugs motivates horizon exploration for other nanoscale designed particles’ implications in gene delivery. In this review we aim to highlight the molecular role of TRAIL in apoptosis and interaction with cancer stem cells (CSCs) self-renewal pathways. Finally, we also aim to discuss the different roles of gene delivery systems, mesenchymal cells, and nanotechnology designs in TRAIL gene delivery.

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Proteome and phosphoproteome profiling of non‐small cell lung cancer cell line A549 treated with TRAIL

Zhong

Yang

et al. 2022

Proteomics

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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is recognized for its promising therapeutic effects against cancer. However, mechanisms underlying the effect of TRAIL on protein expression, signal transduction, and apoptosis induction remain unclear. We surmised that a systematic analysis of the proteome and phosphoproteome associated with TRAIL signaling may help elucidate the mechanisms involved and facilitate the development of therapeutics. Therefore, we investigated the proteome and phosphoproteome of non-small cell lung cancer cell line A549 treated with TRAIL. Our results indicated that 126 proteins and 1684 phosphosites were markedly differentially expressed between the phosphate-buffered saline-and TRAIL-treated groups. The expression at protein and phosphosite levels were not completely consistent. Gene ontology functional analysis revealed that metal ion (zinc) binding was highly affected by TRAIL treatment. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed that almost all pathways that involved differentially expressed phosphosites were associated with apoptosis. We also identified an important kinase, AKT1, and its series of substrates in TRAIL signaling. The results of this study may provide guidance for future research on tumor therapy using TRAIL.

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Silencing Daxx increases the anti-tumor activity of a TRAIL/shRNA Bcl-xL-expressing oncolytic adenovirus through enhanced viral replication and cellular arrest

Cited by 8 publications

References 32 publications

High levels of Daxx due to low cellular levels of HSP25 in murine cancer cells result in inefficient adenovirus replication

High levels of Daxx due to low cellular levels of HSP25 in murine cancer cells result in inefficient adenovirus replication

Role of nanotechnology and gene delivery systems in TRAIL based therapies

Proteome and phosphoproteome profiling of non‐small cell lung cancer cell line A549 treated with TRAIL

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