Small molecule growth inhibitors of human oncogenic gammaherpesvirus infected B‐cells

Dzeng, Richard K.; Jha, Hem Chandra; Lu, Jie; Saha, Abhik; Banerjee, Sagarika; Robertson, Erle S.

doi:10.1016/j.molonc.2014.09.006

Cited by 7 publications

(6 citation statements)

References 51 publications

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“…This prompted us to follow-up on our current data above to more closely understand the link between p21 and NF-kB in KSHV positive cells. Interestingly, in other studies we also observed that small molecules inhibitors targeted EBV and KSHV lymphoma cells through the NF-kB pathway [ 58 ]. Here we analyzed BC-3 cells in the presence of a SNAIL inhibitor, as a KSHV positive cell line compared to the KSHV negative cell line BJAB ( Fig 10A and 10B ).…”

Section: Resultsmentioning

confidence: 87%

KSHV-Mediated Regulation of Par3 and SNAIL Contributes to B-Cell Proliferation

et al. 2016

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Studies have suggested that Epithelial–Mesenchymal Transition (EMT) and transformation is an important step in progression to cancer. Par3 (partitioning-defective protein) is a crucial factor in regulating epithelial cell polarity. However, the mechanism by which the latency associated nuclear antigen (LANA) encoded by Kaposi's Sarcoma associated herpesvirus (KSHV) regulates Par3 and EMTs markers (Epithelial-Mesenchymal Transition) during viral-mediated B-cell oncogenesis has not been fully explored. Moreover, several studies have demonstrated a crucial role for EMT markers during B-cell malignancies. In this study, we demonstrate that Par3 is significantly up-regulated in KSHV-infected primary B-cells. Further, Par3 interacted with LANA in KSHV positive and LANA expressing cells which led to translocation of Par3 from the cell periphery to a predominantly nuclear signal. Par3 knockdown led to reduced cell proliferation and increased apoptotic induction. Levels of SNAIL was elevated, and E-cadherin was reduced in the presence of LANA or Par3. Interestingly, KSHV infection in primary B-cells led to enhancement of SNAIL and down-regulation of E-cadherin in a temporal manner. Importantly, knockdown of SNAIL, a major EMT regulator, in KSHV cells resulted in reduced expression of LANA, Par3, and enhanced E-cadherin. Also, SNAIL bound to the promoter region of p21 and can regulate its activity. Further a SNAIL inhibitor diminished NF-kB signaling through upregulation of Caspase3 in KSHV positive cells in vitro. This was also supported by upregulation of SNAIL and Par3 in BC-3 transplanted NOD-SCID mice which has potential as a therapeutic target for KSHV-associated B-cell lymphomas.

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Section: Resultsmentioning

confidence: 87%

KSHV-Mediated Regulation of Par3 and SNAIL Contributes to B-Cell Proliferation

et al. 2016

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“…Moreover, many cancers are targeted using Aurora kinase and Pim1 inhibitors for reducing tumor burden. A prognostic approach where using small molecules inhibitors targeting key signaling pathways in these viral infected cells may be useful in combination with kinase inhibitors [ 371 ]. Moreover, in vivo studies will be critical for validation of these strategies followed by clinical trials.…”

Section: Discussionmentioning

confidence: 99%

The Role of Gammaherpesviruses in Cancer Pathogenesis

2016

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Worldwide, one fifth of cancers in the population are associated with viral infections. Among them, gammaherpesvirus, specifically HHV4 (EBV) and HHV8 (KSHV), are two oncogenic viral agents associated with a large number of human malignancies. In this review, we summarize the current understanding of the molecular mechanisms related to EBV and KSHV infection and their ability to induce cellular transformation. We describe their strategies for manipulating major cellular systems through the utilization of cell cycle, apoptosis, immune modulation, epigenetic modification, and altered signal transduction pathways, including NF-kB, Notch, Wnt, MAPK, TLR, etc. We also discuss the important EBV latent antigens, namely EBNA1, EBNA2, EBNA3’s and LMP’s, which are important for targeting these major cellular pathways. KSHV infection progresses through the engagement of the activities of the major latent proteins LANA, v-FLIP and v-Cyclin, and the lytic replication and transcription activator (RTA). This review is a current, comprehensive approach that describes an in-depth understanding of gammaherpes viral encoded gene manipulation of the host system through targeting important biological processes in viral-associated cancers.

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“…Recently, we have successfully identified several small molecules inhibitors (NSC65381, NSC10010, NSC16553, and NSC1881) that were able to kill virus positive LCLs as well as EBV negative BL cells (Dzeng et al, 2015). We have also demonstrated that c-Myc and NF-kB are the major signaling molecules targeted through these inhibitors to kill virus positive cells (Dzeng et al, 2015).…”

Section: Treatment Of Ebv Associated Diseasesmentioning

confidence: 99%

“…We have also demonstrated that c-Myc and NF-kB are the major signaling molecules targeted through these inhibitors to kill virus positive cells (Dzeng et al, 2015). Earlier, arsenic trioxide (As2O3) and sodium arsenite (NaAsO2) were also shown to induce cell death in P3HR1 cells (Zebboudj et al, 2014).…”

Section: Treatment Of Ebv Associated Diseasesmentioning

confidence: 99%

Epstein–Barr Virus: Diseases Linked to Infection and Transformation

Jha

Pei

2016

Front. Microbiol.

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Epstein–Barr virus (EBV) was first discovered in 1964, and was the first known human tumor virus now shown to be associated with a vast number of human diseases. Numerous studies have been conducted to understand infection, propagation, and transformation in various cell types linked to human diseases. However, a comprehensive lens through which virus infection, reactivation and transformation of infected host cells can be visualized is yet to be formally established and will need much further investigation. Several human cell types infected by EBV have been linked to associated diseases. However, whether these are a direct result of EBV infection or indirectly due to contributions by additional infectious agents will need to be fully investigated. Therefore, a thorough examination of infection, reactivation, and cell transformation induced by EBV will provide a more detailed view of its contributions that drive pathogenesis. This undoubtedly expand our knowledge of the biology of EBV infection and the signaling activities of targeted cellular factors dysregulated on infection. Furthermore, these insights may lead to identification of therapeutic targets and agents for clinical interventions. Here, we review the spectrum of EBV-associated diseases, the role of the encoded latent antigens, and the switch to latency or lytic replication which occurs in EBV infected cells. Furthermore, we describe the cellular processes and critical factors which contribute to cell transformation. We also describe the fate of B-cells and epithelial cells after EBV infection and the expected consequences which contribute to establishment of viral-associated pathologies.

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Small molecule growth inhibitors of human oncogenic gammaherpesvirus infected B‐cells

Cited by 7 publications

References 51 publications

KSHV-Mediated Regulation of Par3 and SNAIL Contributes to B-Cell Proliferation

KSHV-Mediated Regulation of Par3 and SNAIL Contributes to B-Cell Proliferation

The Role of Gammaherpesviruses in Cancer Pathogenesis

Epstein–Barr Virus: Diseases Linked to Infection and Transformation

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