Co-treatment with arsenic trioxide and ganciclovir reduces tumor volume in a murine xenograft model of nasopharyngeal carcinoma

Sides, Mark D; Sosulski, Meredith L.; Luo, Fayong; Lin, Zhen; Flemington, Erik K.; Lasky, Joseph A.

doi:10.1186/1743-422x-10-152

Cited by 9 publications

(9 citation statements)

References 29 publications

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“…Animal model of the human tumor is an indispensable means to study human tumor. The establishment of the animal model of NPC transplantation tumor provides an ideal experimental material and method for the study of NPC [37]. To further investigate the in vivo effect of circRNA CDR1as on NPC, we established an animal model of NPC xenograft tumor and treated mice with si-CDR1as and miR-7-5p mimic.…”

Section: Discussionmentioning

confidence: 99%

Circular RNA CDR1as sponges miR-7-5p to enhance E2F3 stability and promote the growth of nasopharyngeal carcinoma

et al. 2019

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Background Circular RNA (circRNA) CDR1as plays an important role in the occurrence and development of human tumors. The purpose of this study is to investigate the molecular mechanism of circRNA CDR1as in the development of nasopharyngeal carcinoma (NPC). Methods The mRNA expressions of circRNA CDR1as, miR-7-5p, and E2F3 were detected by qRT-PCR. The effects of circRNA CDR1as, miR-7-5p, and E2F3 on NPC cells were investigated using cell counting kit-8 (CCK8) method, colony formation assay, and representative metabolite assay. The molecular mechanism of circRNA CDR1 in NPC was studied by bioinformatics and luciferase reporter assay. In addition, the biological activity of circRNA CDR1as was also investigated in NPC xenograft tumor mice model. Results The results showed that the circRNA CDR1as expression was significantly up-regulated in NPC tissues by comparison with non-tumor NPE tissues (p < 0.01), suggesting that circRNA CDR1as was associated with poor prognosis in NPC patients. Moreover, circRNA CDR1as could up-regulate E2F3 expression by binding miR-7-5p, and promote the growth and glucose metabolism of NPC cells. Meanwhile, circRNA CDR1as could promote NPC progression through the negative regulation of miR-7-5p in the xenograft tumor model. Conclusion CircRNA CDR1as promoted the occurrence and development of NPCs by successively up-regulating the expression of miR-7-5p and E2F3, suggesting CircRNA CDR1as as a potential target for the treatment of NPC patients. Trial registration The study was approved by the cancer center’s institutional research ethics committee on Oct 18, 2008 (2008GZ2847462)

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Section: Discussionmentioning

confidence: 99%

Circular RNA CDR1as sponges miR-7-5p to enhance E2F3 stability and promote the growth of nasopharyngeal carcinoma

et al. 2019

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“…The switch from latent to lytic stage is driven by EBV immediate-early genes, such as BZLF1 (Zta) in vivo or by various commercial reagents in vitro, for example phorbol 12-myristate 13-acetate [ 1 , 2 ], anti-IgG and anti-IgM [ 3 – 6 ], Ca 2+ ionophore [ 7 ], bone morphogenetic proteins (BMPs) [ 8 ], and transforming growth factor beta 1 (TGF-β1) [ 9 – 11 ]. Recently, we discovered that arsenic trioxide (ATO) activates the EBV lytic cycle in nasopharyngeal carcinoma cells [ 12 ]. In general, the EBV latent cycle is associated with tumorigenesis because latent genes such as LMP1 are oncogenic, whereas the EBV lytic cycle is often considered detrimental to cell survival.…”

Section: Introductionmentioning

confidence: 99%

“…We previously demonstrated that ATO activates the EBV lytic cycle in EBV-positive epithelial cells and inhibits tumor growth in a xenograft model [ 12 ]. In contrast, in this manuscript we did not find that arsenic induced EBV reactivation in Burkitt’s lymphoma cells.…”

Section: Introductionmentioning

confidence: 99%

Arsenic trioxide inhibits EBV reactivation and promotes cell death in EBV-positive lymphoma cells

Yin

Sides

Parsons³

et al. 2017

Virol J

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BackgroundEpstein-Barr Virus (EBV) is associated with hematopoietic malignancies, such as Burkitt’s lymphoma, post-transplantation lymphoproliferative disorder, and diffuse large B-cell lymphoma. The current approach for EBV-associated lymphoma involves chemotherapy to eradicate cancer cells, however, normal cells may be injured and organ dysfunction may occur with currently employed regimens. This research is focused on employing arsenic trioxide (ATO) as EBV-specific cancer therapy takes advantage of the fact the EBV resides within the malignant cells.Methods and resultsOur research reveals that low ATO inhibits EBV gene expression and genome replication. EBV spontaneous reactivation starts as early as 6 h after re-suspending EBV-positive Mutu cells in RPMI media in the absence of ATO, however this does not occur in Mutu cells cultured with ATO. ATO’s inhibition of EBV spontaneous reactivation is dose dependent. The expression of the EBV immediate early gene Zta and early gene BMRF1 is blocked with low concentrations of ATO (0.5 nM – 2 nM) in EBV latency type I cells and EBV-infected PBMC cells. The combination of ATO and ganciclovir further diminishes EBV gene expression. ATO-mediated reduction of EBV gene expression can be rescued by co-treatment with the proteasome inhibitor MG132, indicating that ATO promotes ubiquitin conjugation and proteasomal degradation of EBV genes. Co-immunoprecipitation assays with antibodies against Zta pulls down more ubiquitin in ATO treated cell lysates. Furthermore, MG132 reverses the inhibitory effect of ATO on anti-IgM-, PMA- and TGF-β-mediated EBV reactivation. Thus, mechanistically ATO’s inhibition of EBV gene expression occurs via the ubiquitin pathway. Moreover, ATO treatment results in increased cell death in EBV-positive cells compared to EBV-negative cells, as demonstrated by both MTT and trypan blue assays. ATO-induced cell death in EBV-positive cells is dose dependent. ATO and ganciclovir in combination further enhances cell death specifically in EBV-positive cells.ConclusionATO-mediated inhibition of EBV lytic gene expression results in cell death selectively in EBV-positive lymphocytes, suggesting that ATO may potentially serve as a drug to treat EBV-related lymphomas in the clinical setting.

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“…One proposed method for treating EBV-associated malignancies is the induction of EBV lytic reactivation in latently infected tumor cells (80)(81)(82)(83)(84), which would result in cell susceptibility to cytotoxic antiviral drugs (85). To investigate whether inhibition of LMP1-induced sumoylation results in increased cellular death in response to antiviral therapy, irradiated and mock-irradiated EBV WT-transformed LCLs, EBV dCTAR3-transformed LCLs, and EBV WT-transformed LCLs treated with SUMO inhibitors were treated with ganciclovir (GCV) or a vehicle control (water), and cell death was assayed by trypan blue exclusion (Fig.…”

Section: Lmp1 Ctar3 Is Not Essential For Viral Replicationmentioning

confidence: 99%

LMP1-Induced Sumoylation Influences the Maintenance of Epstein-Barr Virus Latency through KAP1

Bentz

Moss

Whitehurst

et al. 2015

J Virol

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As a herpesvirus, Epstein-Barr virus (EBV) establishes a latent infection that can periodically undergo reactivation, resulting in lytic replication and the production of new infectious virus. Latent membrane protein-1 (LMP1), the principal viral oncoprotein, is a latency-associated protein implicated in regulating viral reactivation and the maintenance of latency. We recently found that LMP1 hijacks the SUMO-conjugating enzyme Ubc9 via its C-terminal activating region-3 (CTAR3) and induces the sumoylation of cellular proteins. Because protein sumoylation can promote transcriptional repression, we hypothesized that LMP1-induced protein sumoylation induces the repression of EBV lytic promoters and helps maintain the viral genome in its latent state. We now show that with inhibition of LMP1-induced protein sumoylation, the latent state becomes less stable or leakier in EBVtransformed lymphoblastoid cell lines. The cells are also more sensitive to viral reactivation induced by irradiation, which results in the increased production and release of infectious virus, as well as increased susceptibility to ganciclovir treatment. We have identified a target of LMP1-mediated sumoylation that contributes to the maintenance of latency in this context: KRABassociated protein-1 (KAP1). LMP1 CTAR3-mediated sumoylation regulates the function of KAP1. KAP1 also binds to EBV OriLyt and immediate early promoters in a CTAR3-dependent manner, and inhibition of sumoylation processes abrogates the binding of KAP1 to these promoters. These data provide an additional line of evidence that supports our findings that CTAR3 is a distinct functioning regulatory region of LMP1 and confirm that LMP1-induced sumoylation may help stabilize the maintenance of EBV latency. IMPORTANCE Epstein-Barr virus (EBV) latent membrane protein-1 (LMP1) plays an important role in the maintenance of viral latency. Previously, we documented that LMP1 targets cellular proteins to be modified by a ubiquitin-like protein (SUMO).We have now identified a function for this LMP1-induced modification of cellular proteins in the maintenance of EBV latency. Because latently infected cells have to undergo viral reactivation in order to be vulnerable to antiviral drugs, these findings identify a new way to increase the rate of EBV reactivation, which increases cell susceptibility to antiviral therapies. E pstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus that causes persistent infection, generally asymptomatic, in over 90% of the world's population. Initially, the virus lytically infects oropharyngeal epithelial cells, producing virions containing linear genomes. The virus also quickly infects B lymphocytes, in which latent infection is established and persists in the form of episomes and subsets of viral latency genes are expressed. Periodically, latent virus can be reactivated and infectious virus is released in saliva (1). The processes that regulate the switch between latent and lytic infection have been studied for many years. One viral gene impli...

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Co-treatment with arsenic trioxide and ganciclovir reduces tumor volume in a murine xenograft model of nasopharyngeal carcinoma

Cited by 9 publications

References 29 publications

Circular RNA CDR1as sponges miR-7-5p to enhance E2F3 stability and promote the growth of nasopharyngeal carcinoma

Circular RNA CDR1as sponges miR-7-5p to enhance E2F3 stability and promote the growth of nasopharyngeal carcinoma

Arsenic trioxide inhibits EBV reactivation and promotes cell death in EBV-positive lymphoma cells

LMP1-Induced Sumoylation Influences the Maintenance of Epstein-Barr Virus Latency through KAP1

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