γ‐Herpesvirus neoplasia: A growing role for COX‐2

Shelby, Bryan D.; Nelson, Anne; Morris, Cindy A.

doi:10.1002/jemt.20226

Cited by 14 publications

(15 citation statements)

References 103 publications

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“…This enzyme is commonly expressed in both premalignant lesions and malignant tumors of e.g., colon, lung, head, neck, and breast (29). In view of the role of COX-2 in tumor development and its up-regulation in herpesvirus-infected cells, this enzyme has been suggested to participate in neoplasia induced by some of the oncogenic herpesviruses, including KSHV and EBV (39). Of interest, HCMV possesses oncomodulatory properties (6) and also up-regulates COX-2 expression within a few hours after infection (32).…”

Section: Discussionmentioning

confidence: 99%

The Human Cytomegalovirus–Encoded Chemokine Receptor US28 Promotes Angiogenesis and Tumor Formation via Cyclooxygenase-2

et al. 2009

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The human cytomegalovirus (HCMV), potentially associated with the development of malignancies, encodes the constitutively active chemokine receptor US28. Previously, we have shown that US28 expression induces an oncogenic phenotype both in vitro and in vivo. Microarray analysis revealed differential expression of genes involved in oncogenic signaling in US28-expressing NIH-3T3 cells. In particular, the expression of cyclooxygenase-2 (COX-2), a key mediator of inflammatory diseases and major determinant in several forms of cancer, was highly up-regulated. US28 induced increases in COX-2 expression via activation of nuclear factor-KB, driving the production of vascular endothelial growth factor. Also, in HCMV-infected cells, US28 contributed to the viral induction of COX-2. Finally, the involvement of COX-2 in US28-mediated tumor formation was evaluated using the COX-2 selective inhibitor Celecoxib. Targeting COX-2 in vivo with Celecoxib led to a marked delay in the onset of tumor formation in nude mice injected with US28-transfected NIH-3T3 cells and a reduction of subsequent growth by repressing the US28-induced angiogenic activity. Hence, the development of HCMV-related proliferative diseases may partially be ascribed to the ability of US28 to activate COX-2.

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Section: Discussionmentioning

confidence: 99%

The Human Cytomegalovirus–Encoded Chemokine Receptor US28 Promotes Angiogenesis and Tumor Formation via Cyclooxygenase-2

et al. 2009

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“…Although COX-2 transcription during KSHV de novo infection was completely repressed by actinomycin D pretreatment, these results should be interpreted with caution as this regulatory mechanism might not be similar in latently infected cells, where abundant levels of COX-2 exist (unpublished results). Aberrant COX-2 expression in latently KSHV-infected endothelial cells (55) and PEL cells (60) indicates that a critical role for posttranscriptional, translational, or posttranslational mechanisms of regulation might be more prevalent than transcriptional mechanisms. Therefore, it becomes relevant to study the role of the 3Ј UTR in the regulation of COX-2 in latently infected cells.…”

Section: Discussionmentioning

confidence: 99%

NFAT and CREB Regulate Kaposi's Sarcoma-Associated Herpesvirus-Induced Cyclooxygenase 2 (COX-2)

Sharma-Walia

Paul

Patel

et al. 2010

J Virol

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COX-2 has been implicated in Kaposi's sarcoma-associated herpesvirus (KSHV) latency and pathogenesis (A. George Paul, N. Sharma-Walia, N. Kerur, C. White, and B. Chandran, Cancer Res. 70:3697-3708, 2010; P. P. Naranatt, H. H. Krishnan, S. R. Svojanovsky, C. Bloomer, S. Mathur, and B. Chandran, Cancer Res. 64:72-84, 2004; N. Sharma-Walia, A. G. Paul, V. Bottero, S. Sadagopan, M. V. Veettil, N. Kerur, and B. Chandran, PLoS Pathog. 6:e1000777, 2010; N. Sharma-Walia, H. Raghu, S. Sadagopan, R. Sivakumar, M. V. Veettil, P. P. Naranatt, M. M. Smith, and B. Chandran, J. Virol. 80:6534-6552, 2006). However, the precise regulatory mechanisms involved in COX-2 induction during KSHV infection have never been explored. Here, we identified cis-acting elements involved in the transcriptional regulation of COX-2 upon KSHV de novo infection. Promoter analysis using human COX-2 promoter deletion and mutation reporter constructs revealed that nuclear factor of activated T cells (NFAT) and the cyclic AMP (cAMP) response element (CRE) modulate KSHV-mediated transcriptional regulation of COX-2. Along with multiple KSHV-induced signaling pathways, infection-induced prostaglandin E2 (PGE2) also augmented COX-2 transcription. Infection of endothelial cells markedly induced COX-2 expression via a cyclosporine A-sensitive, calcineurin/NFAT-dependent pathway. KSHV infection increased intracellular cAMP levels and activated protein kinase A (PKA), which phosphorylated the CRE-binding protein (CREB) at serine 133, which probably led to interaction with CRE in the COX-2 promoter, thereby enhancing COX-2 transcription. PKA selective inhibitor H-89 pretreatment strongly inhibited CREB serine 133, indicating the involvement of a cAMP-PKA-CREB-CRE loop in COX-2 transcriptional regulation. In contrast to phosphatidylinositol 3-kinase and protein kinase C, inhibition of FAK and Src effectively reduced KSHV infection-induced COX-2 transcription and protein levels. Collectively, our study indicates that mediation of COX-2 transcription upon KSHV infection is a paradigm of a complex regulatory milieu involving the interplay of multiple signal cascades and transcription factors. Intervention at each step of COX-2/PGE2 induction can be used as a potential therapeutic target to treat KSHV-associated neoplasm and control inflammatory sequels of KSHV infection.

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“…Pharmacological agents such as nonsteroidal anti-inflammatory drugs target COX-1 and COX-2 (64,75). Moreover, nonsteroidal anti-inflammatory drugs blocking COX and prostaglandin production have been recognized as potentially effective antiviral compounds (63,78,86). COX-2 produces an important inflammatory prostaglandin, prostaglandin E 2 (PGE 2 ), which is a potent immunoregulatory lipid mediator that plays key roles in the regulation of a number of cellular processes, including the acute and chronic inflammatory responses as well as innate immune responses which are generally produced in response to cytokines, mitogens, bacterial lipopolysaccharide (LPS), and viral infections (53,66,74).…”

mentioning

confidence: 99%

Cyclooxygenase 2 Induced by Kaposi's Sarcoma-Associated Herpesvirus Early during In Vitro Infection of Target Cells Plays a Role in the Maintenance of Latent Viral Gene Expression

Sharma-Walia

Raghu

Sadagopan

et al. 2006

J Virol

162

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Infection of human dermal microvascular endothelial (HMVEC-d) cells and human foreskin fibroblast (HFF) cells in vitro by Kaposi's sarcoma-associated herpesvirus (KSHV) provides an excellent in vitro model system to study viral latency. KSHV infection is characterized by the induction of preexisting host signal cascades; sustained expression of the latency-associated open reading frame 73 (ORF73) (LANA-1), ORF72, and K13 genes; transient expression of a limited number of lytic genes, including the lytic cycle switch ORF50 (replication and transcription activator) gene; and reprogramming of host transcriptional machinery regulating a variety of cellular processes, including several proinflammatory responses. The cyclooxygenase 2 (COX-2) gene was one of the host cell genes that was highly up-regulated at 2 and 4 h postinfection (p.i.) of HMVEC-d and HFF cells (P. P. Naranatt, H. H. Krishnan, S. R. Svojanovsky, C. Bloomer, S. Mathur, and B. Chandran, Cancer Res. 64:72-84, 2004). Since COX-2 is an important mediator of inflammatory and angiogenic responses, here, using real-time PCR, Western blot, and immunofluorescence assays, we characterized the COX-2 stimulation and its role in KSHV infection. KSHV induced a robust COX-2 expression, which reached a maximum at 2 h p.i. in HMVEC-d cells and at 8 h p.i. in HFF cells, and significantly higher levels were continuously detected for up to 72 h p.i. Constitutive COX-1 protein levels were not modulated by KSHV infection. Moderate levels of COX-2 were also induced by UV-irradiated KSHV and by envelope glycoproteins gB and gpK8.1A; however, viral gene expression appears to be essential for the increased COX-2 induction. High levels of prostaglandin E2 (PGE2), a COX-2 product, were released in the culture supernatant medium of infected cells. PGE2 synthase, catalyzing the biosynthesis of PGE2, also increased upon infection and inhibition of COX-2 by NS-398, and indomethacin drastically reduced the levels of PGE2 and PGE2 synthase. COX-2 inhibition did not affect KSHV binding, internalization of virus, or the trafficking to the infected cell nuclei. However, latent ORF73 gene expression and ORF73 promoter activity were significantly reduced by COX-2 inhibitors, and this inhibition was relieved by exogenous supplementation with PGE2. In contrast, lytic ORF50 gene expression and ORF50 promoter activity were unaffected. These studies demonstrate that COX-2 and PGE2 play roles in facilitating latent viral gene expression and the establishment and maintenance of latency and suggest that KSHV has evolved to utilize the inflammatory responses induced during infection of endothelial cells for the maintenance of viral latent gene expression.

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γ‐Herpesvirus neoplasia: A growing role for COX‐2

Cited by 14 publications

References 103 publications

The Human Cytomegalovirus–Encoded Chemokine Receptor US28 Promotes Angiogenesis and Tumor Formation via Cyclooxygenase-2

The Human Cytomegalovirus–Encoded Chemokine Receptor US28 Promotes Angiogenesis and Tumor Formation via Cyclooxygenase-2

NFAT and CREB Regulate Kaposi's Sarcoma-Associated Herpesvirus-Induced Cyclooxygenase 2 (COX-2)

Cyclooxygenase 2 Induced by Kaposi's Sarcoma-Associated Herpesvirus Early during In Vitro Infection of Target Cells Plays a Role in the Maintenance of Latent Viral Gene Expression

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