ID: 51: CHEMOTHERAPEUTIC POTENTIAL OF LIPOXINS IN KAPOSI'S SARCOMA AND PRIMARY EFFUSION LYMPHOMA

2016 ◽  
Vol 64 (4) ◽  
pp. 954.3-955
Author(s):  
XM Huang ◽  
AC Hwang ◽  
N Sharma-Walia
Keyword(s):  
Kaposi's Sarcoma ◽  
Cell Cycle Progression ◽  
Therapeutic Potential ◽  
Primary Effusion Lymphoma ◽  
Kaposi’S Sarcoma ◽  
B Cell Lymphoma ◽  
Cell Types ◽  
Body Cavity ◽  
Anti Inflammatory ◽  
Apoptotic Pathways

Current treatments for Kaposi's Sarcoma (KS) and Primary Effusion Lymphoma (PEL) rely on systemic chemotherapeutics developed for non-virus-associated cancers that target DNA replication of all dividing cells. Other treatment methods aim at keeping immune system healthy and infection under control through surgery. All of the above approaches have low efficacy, high cost, and high risk of secondary malignancies especially in immuno-compromised patients. Hence, there is an emerging need to look for alternative treatment focused on KS or PEL host molecules, such as Lipoxins. Lipoxins are anti-inflammatory molecules that can target a variety of pro-inflammatory pathways of KS and PEL. Previous results from our lab have shown that level of ALX receptor (ALXR) does not change after Kaposi's Sarcoma Herpes Virus (KSHV) infection, leading to the potential use of Lipoxins to trigger anti-inflammatory and pro-apoptotic pathways as treatment of KS and PEL.In this study, we investigated downstream signaling in KSHV harboring body cavity B cell lymphoma (BCBL-1) cells induced by Lipoxin treatment to assess its pro-apoptotic effect. We treated 5–10×106 BCBL-1 cells with solvent control (EtOH), Lipoxin (100 mM), or Epilipoxin (100 mM) for 48 and 72 hrs. Downstream phosphorylation of Akt, NF-kB p65, and ERK were assessed using Western blotting and pro-apoptotic gene changes were detected using Real-Time PCR. Cell survival and cell cycle progression was assessed using BrdU FACS analysis. We found that Lipoxin and Epilipoxin treatment downregulated NF-kB and ERK activation via ALXR binding while Akt signaling was not affected. We also found that Lipoxin successfully upregulated pro-apoptotic genes such as BIM-1, BAX, BCL-10, and p53 compared to control. Lipoxin treatment also led to decreased S-phase progression and induction of apoptosis. In conclusion, our study suggests that Lipoxins have therapeutic potential for PEL and should be explored in KS and other PEL cell types.

scholarly journals Nanotechnology Frontiers in γ-Herpesviruses Treatments

2021 ◽  
Vol 22 (21) ◽  
pp. 11407
Author(s):  
Marisa Granato
Keyword(s):  
Kaposi's Sarcoma ◽  
Cell Cycle Progression ◽  
Primary Effusion Lymphoma ◽  
Kaposi’S Sarcoma ◽  
Castleman Disease ◽  
Etiologic Agent ◽  
Barr Virus ◽  
Associated Diseases

Epstein–Barr Virus (EBV) and Kaposi’s sarcoma associated-herpesvirus (KSHV) are γ-herpesviruses that belong to the Herpesviridae family. EBV infections are linked to the onset and progression of several diseases, such as Burkitt lymphoma (BL), nasopharyngeal carcinoma (NPC), and lymphoproliferative malignancies arising in post-transplanted patients (PTDLs). KSHV, an etiologic agent of Kaposi’s sarcoma (KS), displays primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD). Many therapeutics, such as bortezomib, CHOP cocktail medications, and natural compounds (e.g., quercetin or curcumin), are administrated to patients affected by γ-herpesvirus infections. These drugs induce apoptosis and autophagy, inhibiting the proliferative and cell cycle progression in these malignancies. In the last decade, many studies conducted by scientists and clinicians have indicated that nanotechnology and nanomedicine could improve the outcome of several treatments in γ-herpesvirus-associated diseases. Some drugs are entrapped in nanoparticles (NPs) expressed on the surface area of polyethylene glycol (PEG). These NPs move to specific tissues and exert their properties, releasing therapeutics in the cell target. To treat EBV- and KSHV-associated diseases, many studies have been performed in vivo and in vitro using virus-like particles (VPLs) engineered to maximize antigen and epitope presentations during immune response. NPs are designed to improve therapeutic delivery, avoiding dissolving the drugs in toxic solvents. They reduce the dose-limiting toxicity and reach specific tissue areas. Several attempts are ongoing to synthesize and produce EBV vaccines using nanosystems.

scholarly journals Kaposi’s sarcoma-associated herpesvirus latency-associated nuclear antigen dysregulates expression of MCL-1 by targeting FBW7

2021 ◽  
Vol 17 (1) ◽  
pp. e1009179
Author(s):  
Yeong Jun Kim ◽  
Yuri Kim ◽  
Abhishek Kumar ◽  
Chan Woo Kim ◽  
Zsolt Toth ◽  
...  
Keyword(s):  
Kaposi's Sarcoma ◽  
Primary Effusion Lymphoma ◽  
Kaposi’S Sarcoma ◽  
B Cell Lymphoma ◽  
Soft Agar ◽  
Nuclear Antigen ◽  
Ubiquitination Pathway ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
The Stability ◽  
Kaposi’S Sarcoma Associated Herpesvirus

Primary effusion lymphoma (PEL) is an aggressive B cell lymphoma that is etiologically linked to Kaposi’s sarcoma-associated herpesvirus (KSHV). Despite standard multi-chemotherapy treatment, PEL continues to cause high mortality. Thus, new strategies to control PEL are needed urgently. Here, we show that a phosphodegron motif within the KSHV protein, latency-associated nuclear antigen (LANA), specifically interacts with E3 ubiquitin ligase FBW7, thereby competitively inhibiting the binding of the anti-apoptotic protein MCL-1 to FBW7. Consequently, LANA-FBW7 interaction enhances the stability of MCL-1 by preventing its proteasome-mediated degradation, which inhibits caspase-3-mediated apoptosis in PEL cells. Importantly, MCL-1 inhibitors markedly suppress colony formation on soft agar and tumor growth of KSHV+PEL/BCBL-1 in a xenograft mouse model. These results strongly support the conclusion that high levels of MCL-1 expression enable the oncogenesis of PEL cells and thus, MCL-1 could be a potential drug target for KSHV-associated PEL. This work also unravels a mechanism by which an oncogenic virus perturbs a key component of the ubiquitination pathway to induce tumorigenesis.

scholarly journals Spectrum of Kaposi's Sarcoma-Associated Herpesvirus, or Human Herpesvirus 8, Diseases

2002 ◽  
Vol 15 (3) ◽  
pp. 439-464 ◽  
Author(s):  
Dharam V. Ablashi ◽  
Louise G. Chatlynne ◽  
James E. Whitman, ◽  
Ethel Cesarman
Keyword(s):  
Dna Sequences ◽  
Kaposi's Sarcoma ◽  
Primary Effusion Lymphoma ◽  
Human Herpesvirus ◽  
Kaposi’S Sarcoma ◽  
B Cell Lymphoma ◽  
Human Herpesvirus 8 ◽  
Herpesvirus 8 ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

SUMMARY Human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma-associated herpesvirus (KSHV), discovered in 1994, is a human rhadinovirus (gamma-2 herpesvirus). Unlike other human herpesviruses (herpes simplex virus, Epstein-Barr virus, varicella-zoster virus, cytomegalovirus, HHV-6, and HHV-7), it is not widespread in the general population and has many unique proteins. HHV-8 is strongly associated with all subtypes of Kaposi's sarcoma (KS), multicentric Castleman's disease, and a rare form of B-cell lymphoma, primary effusion lymphoma. In addition, HHV-8 DNA sequences have been found in association with other diseases, but the role of the virus in these diseases is largely unconfirmed and remains controversial. The seroprevalence of HHV-8, based on detection of latent and lytic proteins, is 2 to 5% in healthy donors except in certain geographic areas where the virus is endemic, 80 to 95% in classic KS patients, and 40 to 50% in HIV-1 patients without KS. This virus can be transmitted both sexually and through body fluids (e.g., saliva and blood). HHV-8 is a transforming virus, as evidenced by its presence in human malignancies, by the in vitro transforming properties of several of its viral genes, and by its ability to transform some primary cells in culture. It is not, however, sufficient for transformation, and other cofactors such as immunosuppressive cytokines are involved in the development of HHV-8-associated malignancies. In this article, we review the biology, molecular virology, epidemiology, transmission, detection methods, pathogenesis, and antiviral therapy of this newly discovered human herpesvirus.

scholarly journals Kaposi's sarcoma-associated herpesvirus (KSHV or HHV8) in primary effusion lymphoma: ultrastructural demonstration of herpesvirus in lymphoma cells

Blood ◽  
1996 ◽  
Vol 87 (12) ◽  
pp. 4937-4943 ◽  
Author(s):  
W Said ◽  
K Chien ◽  
S Takeuchi ◽  
T Tasaka ◽  
H Asou ◽  
...  
Keyword(s):  
Kaposi's Sarcoma ◽  
Primary Effusion Lymphoma ◽  
Kaposi’S Sarcoma ◽  
Body Cavity ◽  
Molecular Evidence ◽  
A Cell ◽  
Malignant Effusions ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Epstein Barr ◽  
Kaposi’S Sarcoma Associated Herpesvirus

Recent molecular evidence suggests an association with a new herpesvirus, Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8), and primary effusion lymphomas (PELs). PELs have a characteristic morphology, phenotype, and clinical presentation, with malignant effusions in the absence of a contiguous solid tumor mass. We have established a cell line (KS-1) from a KSHV-positive human immunodeficiency virus (HIV)-negative patient with pleural cavity-based lymphoma that was passaged into triple-immunodeficient BNX mice. In contrast to cell lines from body cavity-based lymphomas derived from HIV-positive individuals that contain both KSHV and Epstein Barr viral genome, these cells contain only KSHV, allowing for uncontaminated virologic studies. Ultrastructural examination identified malignant cells with features of late differentiating B cells (immunoblasts). Cells with viral cytopathic effect contained typical 110-nm intranuclear herpesvirus nucleocapsids and complete cytoplasmic virions, confirming the association of PEL with KSHV.

scholarly journals HHV-8-Associated Lymphoproliferative Disorders and Pathogenesis in an HIV-Positive Patient

2019 ◽  
Vol 2019 ◽  
pp. 1-6 ◽  
Author(s):  
Carlo Guerrero ◽  
Tania Jain ◽  
Katalin Kelemen
Keyword(s):  
Kaposi's Sarcoma ◽  
Primary Effusion Lymphoma ◽  
Clinical Manifestations ◽  
Human Herpesvirus ◽  
Kaposi’S Sarcoma ◽  
B Cell Lymphoma ◽  
Lymphoproliferative Disorders ◽  
World Health ◽  
Hiv Positive ◽  
Health Organization

Human herpesvirus 8 (HHV-8), also known as Kaposi’s sarcoma-associated herpesvirus, is a DNA oncovirus known for its role in the development of Kaposi’s sarcoma (KS) and several lymphoproliferative disorders (LPDs). HHV-8 promotes lymphoproliferation via the activation of the interleukin-6 receptor signaling pathway, as well as a host of other regulatory mechanisms. The spectrum of HHV-8-associated LPDs is increasing. The World Health Organization has recently updated the classification of HHV-8-associated LPDs by introducing HHV-8-positive germinotropic LPD (GLPD) in addition to the previously recognized entities of HHV-8-positive diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), primary effusion lymphoma (PEL), and HHV-8-positive multicentric Castleman’s disease (MCD). We present here a case of an HIV-positive woman with a history of KS, who later developed three HHV-8-associated LPDs, including HHV-8-positive MCD, PEL, and GLPD. To the best of our knowledge, this is the first reported case of a patient with this combination of individually rare HHV-8-associated LPDs. This case illustrates the spectrum and the sequential development of the different clinical manifestations of HHV-8-associated diseases. Detection of HHV-8 can have clinical significance in the diagnosis and management of certain HHV-8-associated conditions. Recently discovered variants of HHV-8-associated LPDs indicate that this group represents a diverse spectrum of disorders, whose classification may require further refinement beyond the currently recognized entities.

scholarly journals The K1 Protein of Kaposi's Sarcoma-Associated Herpesvirus Activates the Akt Signaling Pathway

2004 ◽  
Vol 78 (4) ◽  
pp. 1918-1927 ◽  
Author(s):  
Christine C. Tomlinson ◽  
Blossom Damania
Keyword(s):  
Kaposi's Sarcoma ◽  
Cell Cycle Progression ◽  
B Lymphocyte ◽  
Primary Effusion Lymphoma ◽  
Kaposi’S Sarcoma ◽  
Cellular Transformation ◽  
Cell Receptor ◽  
Focus Formation ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV) has been implicated in Kaposi's sarcoma, as well as in primary effusion lymphoma and multicentric Castleman's disease. The K1 protein of KSHV has been shown to induce cellular transformation and focus formation and to deregulate B-lymphocyte signaling pathways by functionally mimicking the activated B-cell receptor complex. Here we show that expression of K1 in B lymphocytes targets the phosphatidylinositol-3 kinase pathway, leading to the activation of the Akt kinase and the inhibition of the phosphatase PTEN. We also demonstrate that activation of Akt by the K1 protein leads to the phosphorylation and inhibition of members of the forkhead (FKHR) transcription factor family, which are key regulators of cell cycle progression and apoptosis. We demonstrate that K1 can inhibit apoptosis induced by the FKHR proteins and by stimulation of the Fas receptor. Our observations suggest that the K1 viral protein promotes cell survival pathways and may contribute to KSHV pathogenesis by preventing virally infected cells from undergoing apoptosis prematurely.

scholarly journals The Kaposi's Sarcoma-Associated Herpesvirus LANA Protein Stabilizes and Activates c-Myc

2007 ◽  
Vol 81 (19) ◽  
pp. 10451-10459 ◽  
Author(s):  
Jianyong Liu ◽  
Heather J. Martin ◽  
Gangling Liao ◽  
S. Diane Hayward
Keyword(s):  
Cell Cycle ◽  
Kaposi's Sarcoma ◽  
Cell Cycle Progression ◽  
Glycogen Synthase ◽  
Primary Effusion Lymphoma ◽  
Kaposi’S Sarcoma ◽  
Nuclear Antigen ◽  
Erk Phosphorylation ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

ABSTRACT The Kaposi's sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA) protein is functionally pleiotropic. LANA contributes to KSHV-associated pathogenesis, in part, by increasing entry of cells into S phase through a process that is driven by LANA interaction with the serine-threonine kinase glycogen synthase kinase 3 (GSK-3) and stabilization of β-catenin. We now show that LANA affects the activity of another protein involved in cell cycle regulation, c-Myc. Sequencing of c-Myc coding sequences revealed that c-Myc in KSHV-positive primary effusion lymphoma (PEL) cell lines is wild type in the N-terminal region that regulates c-Myc protein stability. Despite this, c-Myc in PEL cells is stabilized. In LANA-expressing cells, inactivation of nuclear GSK-3 reduced phosphorylation of c-Myc at Thr58 and contributed to c-Myc stabilization by decreasing c-Myc ubiquitination. Phosphorylation of c-Myc on Ser62 also affects c-Myc stability and function. We now show that LANA increases the level of phosphorylated extracellular signal-regulated kinase 1 (ERK1) and increases ERK phosphorylation of c-Myc on Ser62. LANA also interacted with c-Myc, and c-Myc amino acids 147 to 220 were required for this interaction. LANA (L1006P) retained the ability to bind to c-Myc and activate ERK1, indicating that these events did not require LANA interaction with GSK-3. Thus, LANA stabilizes c-Myc; prevents the phosphorylation of c-Myc at Thr58, an event that promotes Myc-induced apoptosis; and independently stimulates phosphorylation of c-Myc at Ser62, an event that transcriptionally activates c-Myc. LANA-mediated manipulation of c-Myc function is likely to contribute to KSHV-associated tumorigenesis through the induction of c-Myc regulated cellular genes, as well as by the stimulation of cell cycle progression.

scholarly journals Altering the Anti-inflammatory Lipoxin Microenvironment: a New Insight into Kaposi's Sarcoma-Associated Herpesvirus Pathogenesis

2016 ◽  
Vol 90 (24) ◽  
pp. 11020-11031 ◽  
Author(s):  
Jayashree A. Chandrasekharan ◽  
Xiao M. Huang ◽  
Alexander C. Hwang ◽  
Neelam Sharma-Walia
Keyword(s):  
Kaposi's Sarcoma ◽  
Therapeutic Potential ◽  
Kaposi’S Sarcoma ◽  
Host Cells ◽  
Mirna Cluster ◽  
Lipoxin A4 ◽  
Anti Inflammatory ◽  
Inflammatory Molecules ◽  
Insight Into

ABSTRACTLipoxins are host anti-inflammatory molecules that play a vital role in restoring tissue homeostasis. The efficacy of lipoxins and their analog epilipoxins in treating inflammation and its associated diseases has been well documented. Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL) are two well-known inflammation related diseases caused by Kaposi's sarcoma-associated herpesvirus (KSHV). Controlling inflammation is one of the strategies adopted to treat KS and PEL, a primary motivation for exploring and evaluating the therapeutic potential of using lipoxins. This study documents how KSHV manipulates and downregulates the secretion of the anti-inflammatory lipoxin A4 in host cells and the viral factors involved in this process usingin vitroKS and PEL cells as models. The presence of the lipoxin A4 receptor/formyl peptidyl receptor (ALX/FPR) in KS patient tissue sections andin vitroKS and PEL cell models offers a novel possibility for treating KS and PEL with lipoxins. Treatingde novoKSHV-infected endothelial cells with lipoxin and epilipoxin creates an anti-inflammatory environment by decreasing the levels of NF-κB, AKT, ERK1/2, COX-2, and 5-lipoxygenase. Lipoxin treatment on CRISPR/CAS9 technology-mediated ALX/FPR gene deletion revealed the importance of the lipoxin receptor ALX for effective lipoxin signaling. A viral microRNA (miRNA) cluster was identified as the primary factor contributing to the downregulation of lipoxin A4 secretion in host cells. The KSHV miRNA cluster probably targets enzyme 15-lipoxygenase, which is involved in lipoxin A4 synthesis. This study provides a new insight into the potential treatment of KS and PEL using nature's own anti-inflammatory molecule, lipoxin.IMPORTANCEKSHV infection has been shown to upregulate several host proinflammatory factors, which aid in its survival and pathogenesis. The influence of KSHV infection on anti-inflammatory molecules is not well studied. Since current treatment methods for KS and PEL are fraught with unwanted side effects and low efficiency, the search for new therapeutics is therefore imperative. The use of nature's own molecule lipoxin as a drug is promising. This study opens up new domains in KSHV research focusing on how the virus modulates lipoxin secretion and warrants further investigation of the therapeutic potential of lipoxin usingin vitrocell models for KS and PEL.

scholarly journals Distinct Biology of Kaposi’s Sarcoma-Associated Herpesvirus from Primary Lesions and Body Cavity Lymphomas

1998 ◽  
Vol 72 (12) ◽  
pp. 10073-10082 ◽  
Author(s):  
Jacques Friborg ◽  
Wing-Pui Kong ◽  
C. Clay Flowers ◽  
Scarlett L. Flowers ◽  
Yongnian Sun ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Line ◽  
Kaposi's Sarcoma ◽  
Cell Lymphoma ◽  
Kaposi’S Sarcoma ◽  
B Cell Lymphoma ◽  
Body Cavity ◽  
293 Cells ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

ABSTRACT The DNA sequence for Kaposi’s sarcoma-associated herpesvirus was originally detected in Kaposi’s sarcoma biopsy specimens. Since its discovery, it has been possible to detect virus in cell lines established from AIDS-associated body cavity-based B-cell lymphoma and to propagate virus from primary Kaposi’s sarcoma lesions in a human renal embryonic cell line, 293. In this study, we analyzed the infectivity of Kaposi’s sarcoma-associated herpesvirus produced from these two sources. Viral isolates from cultured cutaneous primary KS cells was transmitted to an Epstein-Barr virus-negative Burkitt’s B-lymphoma cell line, Louckes, and compared to virus induced from a body cavity-based B-cell lymphoma cell line. While propagation of body cavity-based B-cell lymphoma-derived virus was not observed in 293 cell cultures, infection with viral isolates obtained from primary Kaposi’s sarcoma lesions induced injury in 293 cells typical of herpesvirus infection and was associated with apoptotic cell death. Interestingly, transient overexpression of the Kaposi’s sarcoma-associated herpesvirus v-Bcl-2 homolog delayed the process of apoptosis and prolonged the survival of infected 293 cells. In contrast, the broad-spectrum caspase inhibitors Z-VAD-fmk and Z-DEVD-fmk failed to protect infected cell cultures, suggesting that Kaposi’s sarcoma-associated herpesvirus-induced apoptosis occurs through a Bcl-2-dependent pathway. Kaposi’s sarcoma-associated herpesvirus isolates from primary Kaposi’s sarcoma lesions and body cavity-based lymphomas therefore may differ and are likely to have distinct contributions to the pathophysiology of Kaposi’s sarcoma.

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