Abstract
Kaposi's sarcoma (KS) is a mesenchymal tumour, which is caused by Kaposi's sarcoma herpesvirus (KSHV) and develops under inflammatory conditions. KSHV-infected endothelial spindle cells, the neoplastic cells in KS, show increased invasiveness, attributed to the elevated expression of metalloproteinases (MMPs) and cyclooxygenase-2 (COX-2). The majority of these spindle cells harbour latent KSHV genomes, while a minority undergoes lytic reactivation with subsequent production of new virions and viral or cellular chemo- and cytokines, which may promote tumour invasion and dissemination. In order to better understand KSHV pathogenesis, we investigated cellular mechanisms underlying the lytic reactivation of KSHV. Using a combination of small molecule library screening and siRNA silencing we found a STE20 kinase family member, MAP4K4, to be involved in KSHV reactivation from latency and to contribute to the invasive phenotype of KSHV-infected endothelial cells by regulating COX-2, MMP-7, and MMP-13 expression. This kinase is also highly expressed in KS spindle cells in vivo. These findings suggest that MAP4K4, a known mediator of inflammation, is involved in KS aetiology by regulating KSHV lytic reactivation, expression of MMPs and COX-2, and, thereby modulating invasiveness of KSHV-infected endothelial cells.
Highlights
Kaposi’s sarcoma (KS) is a mesenchymal tumour caused by Kaposi’s sarcoma herpesvirus (KSHV) [1], which originates from blood and lymphatic vessels and develops under the influence of inflammatory cytokines [2,3,4]
When comparing the effects of commercially available p38 inhibitors with compounds in the VICHEM library, we noted that p38 inhibitors SB202190, SB203580, VX745, SKF86002, SB220025, and a derivative of SB220025 (VI18802) differed in their ability to block KSHV reactivation, as shown by their effect on the expression of KSHV envelope glycoprotein K8.1, their ability to inhibit the phosphorylation of MK2, a p38 target, seemed comparable
To extend our observations, which were obtained with the immortalized endothelial cell line HuAR2T, to primary endothelial cells, we investigated the role of MAP4K4 in the invasiveness of human umbilical vein endothelial cells (HUVECs) following their infection with rKSHV.219
Summary
Kaposi’s sarcoma (KS) is a mesenchymal tumour caused by Kaposi’s sarcoma herpesvirus (KSHV) [1], which originates from blood and lymphatic vessels and develops under the influence of inflammatory cytokines [2,3,4]. KSHV-infected spindle cells, which were shown to be of vascular or lymphatic endothelial origin, represent the main proliferative element in KS and are the distinctive histological signature of advanced KS tumours [10,11]. KS spindle cells were shown to have increased invasiveness [13], which has been attributed to the enhanced expression of several matrix metalloproteinases (MMPs) [14], including MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, and MMP-13 [13,15,16]. Increased COX-2 expression in inflammation-driven tumours contributes to neoangiogenesis and activates MMPs, which promote invasiveness [21,22]. Several KSHV proteins were shown to enhance COX-2 expression, including K15 [25], and vGPCR [26]. This could explain how KSHV may increase COX-2 gene expression
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