Lenalidomide, Thalidomide, and Pomalidomide Reactivate the Epstein–Barr Virus Lytic Cycle through Phosphoinositide 3-Kinase Signaling and Ikaros Expression

Jones, Richard J.; Iempridee, Tawin; Wang, Xiaobin; Lee, Hans C.; Mertz, Janet E.; Kenney, Shannon C.; Lin, Heather C.; Baladandayuthapani, Veerabhadran; Dawson, Christopher W.; Shah, Jatin J.; Weber, Donna M.; Orłowski, Robert Z.

doi:10.1158/1078-0432.ccr-15-2242

Cited by 43 publications

(37 citation statements)

References 46 publications

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“…S5E, lanes 4-6). Although Pom has been reported to induce EBV lytic replication in certain other EBV-infected cell lines such as B95.8 and Daudi, 48 we did not detect induction of lytic replication (assessed by BMRF1 induction) in Akata cells by Pom in these experiments (Fig. S5E, lanes 1-3), nor did it have a substantial effect on the levels of BMRF1 lytic protein induced by anti-human IgG (Fig S6E, lanes 4-6).…”

Section: Pom Upregulates Surface Markers In Ebv-infected Cell Linesmentioning

confidence: 52%

Pomalidomide increases immune surface marker expression and immune recognition of oncovirus-infected cells

et al. 2018

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Most chronic viruses evade T-cell and natural killer (NK) immunity through downregulation of immune surface markers. Previously we showed that Pomalidomide (Pom) increases surface expression of major histocompatibility complex class I (MHC-I) in Kaposi sarcoma-associated herpesvirus-infected latent and lytic cells and restores ICAM-1 and B7-2 in latent cells. We explored the ability of Pom to increase immune surface marker expression in cells infected by other chronic viruses, including human T-cell leukemia virus type-1 (HTLV-1), Epstein-Barr virus (EBV), human papilloma virus (HPV), Merkel cell polyoma virus (MCV), and human immunodeficiency virus type-1 (HIV-1). Pom increased MHC-1, ICAM-1, and B7-2/CD86 in immortalized T-cell lines productively infected with HTLV-1 and also significantly increased their susceptibility to NK cell-mediated cytotoxicity. Pom enhancement of MHC-I and ICAM-1 in primary cells infected with HTLV-1 was abrogated by knockout of HTLV-1 orf-1. Pom increased expression of ICAM-1, B7-2 and MHC class I polypeptide related sequence A (MICA) surface expression in the EBV-infected Daudi cells and increased their T-cell activation and susceptibility to NK cells. Moreover, Pom increased expression of certain of these surface markers on Akata, Raji, and EBV lymphoblastic cell lines. The increased expression of immune surface markers in these virus-infected lines was generally associated with a decrease in IRF4 expression. By contrast, Pom treatment of HPV, MCV and HIV-1 infected cells did not increase these immune surface markers. Pom and related drugs may be clinically beneficial for the treatment of HTLV-1 and EBV-induced tumors by rendering infected cells more susceptible to both innate and adaptive host immune responses.

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Section: Pom Upregulates Surface Markers In Ebv-infected Cell Linesmentioning

confidence: 52%

Pomalidomide increases immune surface marker expression and immune recognition of oncovirus-infected cells

et al. 2018

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“…Numerous studies have reported that the PI3K/AKT pathway plays an important role in metastasis through the regulation of EMT [23][24][25]. Therefore, the PI3K inhibitor LY294002 [26][27][28][29] was used to detect the effect of the PI3K/AKT pathway on AGK-induced RCC proliferation and metastasis. As shown in Fig.…”

Section: Agk Promotes Rcc Proliferation and Metastasis Via The Pi3k/amentioning

confidence: 99%

Acylglycerol kinase promotes tumour growth and metastasis via activating the PI3K/AKT/GSK3β signalling pathway in renal cell carcinoma

Zhu

Zhong

et al. 2020

J Hematol Oncol

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Background: Clinically, the median survival in patients with metastatic renal cell carcinoma (RCC) was only 6-12 months and a 5-year survival rate of less than 20%. Therefore, an in-depth study of the molecular mechanisms involved in RCC is of great significance for improving the survival of patients with advanced RCC. Acylglycerol kinase (AGK) is a newly discovered lipid kinase that has been reported to be a potent oncogene that may be involved in the regulation of malignant progression in a variety of tumours. However, the expression and biological characteristics of the AGK gene in RCC remain unclear. Methods: AGK expression was quantified by quantitative real-time PCR, Western blotting and immunohistochemistry in RCC cell lines and paired patient tissues. Kaplan-Meier method and Cox proportional hazards models were used to evaluate the prognostic value of AGK in human RCC tissue samples. Chi-squared test was performed to analyse the correlation between AGK expression and the clinicopathological features. Stable overexpression and knockdown of AGK in RCC cells was constructed with lentivirus. The oncogenic effects of AGK in human RCC progression were investigated using assays of colony formation, anchorage-independent growth, EdU assay, cell cycle analysis, wound-healing, trans-well analysis and xenograft tumour model. GSEA and KEGG analysis were conducted to detect the potential pathway of AGK involved in RCC. These results were further confirmed using the luciferase reporter assays, immunofluorescence and in vivo experiments. Results: AGK expression is significantly elevated in RCC and closely related to the malignant development and poor prognosis in RCC patients. By in vitro and in vivo experiments, AGK was shown to enhance the proliferation of RCC cells by promoting the transition from the G1 phase to the S phase in the cell cycle and to enhance the migration and invasion by promoting epithelial-mesenchymal transition. By activating the PI3K/AKT/GSK3β signalling pathway in RCC, AGK can increase nuclear accumulation of β-catenin, which further upregulated TCF/LEF transcription factor activity. Conclusions: AGK promotes the progression of RCC via activating the PI3K/AKT/GSK3β signalling pathway and might be a potential target for the further research of RCC.

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“…A variety of strategies to induce lytic viral gene expression so as to facilitate the killing of EBV-associated tumors have been investigated for many years (3-5, 7, 26-31). In some approaches, the hope is that a lytic inducer will activate a viral thymidine kinase or protein kinase that will phosphorylate ganciclovir, poisoning the cellular DNA polymerase such that mitotic cells will be killed (5,7,(31)(32)(33). Other strategies have aimed at the upregulation of immunodominant viral antigens recognized by cytotoxic T cells or the selective concentration of radiopharmaceuticals in tumor tissue (3,4).…”

Section: Discussionmentioning

confidence: 99%

Pharmacologic Activation of Lytic Epstein-Barr Virus Gene Expression without Virion Production

Lee

Kosowicz

Hayward

et al. 2019

J Virol

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Several therapeutic strategies targeting Epstein-Barr virus (EBV)-associated tumors involve upregulation of viral lytic gene expression. Evidence has been presented that the unfolded protein response (UPR) leads to EBV lytic gene expression. Clofoctol, an antibacterial antibiotic, has been reported to upregulate the UPR in prostate cancer cell lines and to slow their growth. We investigated the effects of clofoctol on an EBV-positive Burkitt lymphoma cell line and confirmed the upregulation of all three branches of the UPR and activation of EBV lytic gene expression. While immediate early, early, and late EBV RNAs were all upregulated, immediate early and early viral proteins but not late viral proteins were expressed. Furthermore, infectious virions were not produced. The use of clofoctol in combination with a protein kinase R-like endoplasmic reticulum kinase inhibitor led to expression of late viral proteins. The effects of clofoctol on EBV lytic protein upregulation were not limited to lymphoid tumor cell lines but also occurred in naturally infected epithelial gastric cancer and nasopharyngeal cancer cell lines. An agent that upregulates lytic viral protein expression but that does not lead to the production of infectious virions may have particular value for lytic induction strategies in the clinical setting. IMPORTANCE Epstein-Barr virus is associated with many different cancers. In these cancers the viral genome is predominantly latent; i.e., most viral genes are not expressed, most viral proteins are not synthesized, and new virions are not produced. Some strategies for treating these cancers involve activation of lytic viral gene expression. We identify an antibacterial antibiotic, clofoctol, that is an activator of EBV lytic RNA and protein expression but that does not lead to virion production.

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Lenalidomide, Thalidomide, and Pomalidomide Reactivate the Epstein–Barr Virus Lytic Cycle through Phosphoinositide 3-Kinase Signaling and Ikaros Expression

Cited by 43 publications

References 46 publications

Pomalidomide increases immune surface marker expression and immune recognition of oncovirus-infected cells

Pomalidomide increases immune surface marker expression and immune recognition of oncovirus-infected cells

Acylglycerol kinase promotes tumour growth and metastasis via activating the PI3K/AKT/GSK3β signalling pathway in renal cell carcinoma

Pharmacologic Activation of Lytic Epstein-Barr Virus Gene Expression without Virion Production

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