| Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS) and Body cavity B cell lymphoma (BCBL). Our earlier studies had shown that de novo KSHV infection induces the pro-inflammatory molecule COX-2 and its metabolite PGE2. COX-2 inhibition down-regulated the gene expression of major KSHV latency gene LANA-1 and exogenous PGE2 reversed this effect. Therefore, I hypothesized that COX-2, PGE2, and PGE2/EP receptors play significant roles in KSHV latency.;In the first part of the study, I examined the role of PGE2/EP receptors in KSHV latency program. Microsomal prostaglandin E2 synthase (mPGES), PGE2 and its receptors (EP1, EP2, EP3, and EP4) were detected in KS lesions with the distinct staining of EP2/EP4 in KS lesions. In latently infected endothelial TIVE-LTC cells, EP receptor antagonists down-regulated LANA-1 expression as well as Ca2+ signaling, p-Src, p-PI3K, p-PKC&zgr;/lambda, and p-NF-kappaB, which are also some of the signal molecules proposed to be important in KS pathogenesis. Exogenous PGE2 and EP receptor agonists induced the LANA-1 promoter in 293 cells, and YY1, Sp1, Oct-1, Oct-6, C/EBP and c-Jun transcription factors appear to be involved in this induction. PGE2/EP receptor induced LANA-1 promoter activity was down-regulated significantly by the inhibition of Ca2+ signaling, p-Src, p-PI3K, p-PKC&zgr;/lambda, and p-NF-kappaB.;In the second part of the study, I examined the chemotherapeutic potential of blocking COX-2 in BCBL, an aggressive AIDS-linked KSHV-associated non-Hodgkin's-lymphoma, which has no specific treatments. Nimesulide, a COX-2 specific inhibitor, induced sustained cell death and G1 arrest in BCBL-1 cells and down-regulated KSHV latent genes LANA-1 and vFLIP, LANA-1/p53 interaction, p-Akt and p-GSK-3beta, angiogenic factor VEGF C, BCBL defining genes syndecan-1, aquaporin-3, and vitamin-D3 receptor (VDR), and cell cycle proteins cyclins E/A and cdc25C. My studies thus demonstrate that the anti-survival consequence of nimesulide on BCBL is due to its combined anti-viral/inflammatory/cancer effects such as downregulation of KSHV-latent genes, latent LANA-1 interaction with p53, cell-survival proteins and activation of p53/p21 tumor-suppressor pathway. Furthermore, the inhibition of syndecan-1, aquaporin-3, and VDR provides novel insights into COX-2's potential role in proteoglycan-signaling, ATP-metabolism, and chromatin remodeling, respectively.;Overall, my results implicate the inflammatory PGE2/EP receptors and the associated signaling molecules in herpes virus latency and uncover a novel paradigm that demonstrates the evolution of KSHV genome plasticity to utilize inflammatory response for its survival advantage of maintaining latent gene expression. These studies also suggest that potential use of anti-COX-2 and anti-EP receptor therapy may not only ameliorate the chronic inflammation associated with KS but could also lead to elimination of the KSHV latent infection and the associated KS lesions. Consequently, the second part of my study provides a comprehensive molecular framework linking COX-2 with BCBL pathogenesis and identifies the chemotherapeutic potential of nimesulide in treating BCBL. Additionally, correlation between COX-2 expression and poor NHL prognosis suggests the study's potential as a therapeutic model for similar NHLs. |
