COX-2/PGE2: molecular ambassadors of Kaposi's sarcoma-associated herpes virus oncoprotein-v-FLIP.
COX-2/PGE2: molecular ambassadors of Kaposi's sarcoma-associated herpes virus oncoprotein-v-FLIP.
复制标题
DOI：
10.1038/oncsis.2012.5
复制
发表时间：
2012-04-02
期刊：
影响因子：
6.2
通讯作者：
Paul, A. G.
中科院分区：
文献类型：
--
作者：
Sharma-Walia, N.;Patel, K.;Chandran, K.;Marginean, A.;Bottero, V.;Kerur, N.;Paul, A. G.
卡波西肉瘤疱疹病毒（KSHV）潜伏癌蛋白病毒FLICE（FADD样干扰素转化酶）样抑制蛋白（v-FLIP）或K13（NF-κB的强效激活剂）在KSHV潜伏期和肿瘤发生中具有明确的作用。KSHV诱导的考克斯-2代表了KSHV促进潜伏期和炎症/血管生成/侵袭的新策略。在这里，我们证明v-FLIP/K13通过诱导宿主蛋白考克斯-2及其炎症代谢产物PGE 2以NF-κ B依赖的方式促进致瘤作用。除了我们以前的研究表明考克斯-2/PGE 2在KSHV潜伏启动子和潜伏基因表达的转录调控中的作用外，目前的研究增加了复杂性，尽管拉娜-1（潜伏相关核抗原）利用考克斯-2/PGE 2作为其转录调节的关键因子，KSHV潜伏簇中的v-FLIP/K13基因在感染细胞中维持连续的考克斯-2/PGE 2水平。我们证明，考克斯-2抑制，通过其化学抑制剂（NS-398或塞来昔布），减少v-FLIP/K13介导的NF-κB诱导，细胞外基质（ECM）相互作用介导的信号，线粒体抗氧化酶锰超氧化物歧化酶（MnSOD）水平，并随后下调凋亡诱导的细胞凋亡（失巢凋亡）的阻力。vFLIP表达介导细胞因子的分泌，梭形细胞分化激活p38、RSK、FAK、Src、Akt和Rac 1-GT3的磷酸化。v-FLIP/K13-HMVECs中的考克斯-2抑制减少了炎症和侵袭/转移相关基因，沿着通过调节“外在”和“内在”细胞死亡途径减少的锚定非依赖性集落形成。v-FLIP/K13-HMVEC细胞中的考克斯-2阻断剂显著增加了由去除微环境中分泌的必需生长/存活因子诱导的细胞死亡。从考克斯-2标记物处理的v-FLIP/K13-HMVEC细胞的锚定非依赖性集落获得的转化细胞表达较低水平的内皮-间充质转化基因如slug、snail和twist，以及较高水平的肿瘤抑制基因E-钙粘蛋白表达。总之，我们的研究提供了强有力的证据，FDA批准的考克斯-2抑制剂在阻断与KSHV的致癌蛋白v-FLIP/K13相关的致瘤事件方面具有巨大的潜力。
Kaposi's sarcoma herpesvirus (KSHV) latent oncoprotein viral FLICE (FADD-like interferon converting enzyme)-like inhibitory protein (v-FLIP) or K13, a potent activator of NF-κB, has well-established roles in KSHV latency and oncogenesis. KSHV-induced COX-2 represents a novel strategy employed by KSHV to promote latency and inflammation/angiogenesis/invasion. Here, we demonstrate that v-FLIP/K13 promotes tumorigenic effects via the induction of host protein COX-2 and its inflammatory metabolite PGE2 in an NF-κB-dependent manner. In addition to our previous studies demonstrating COX-2/PGE2's role in transcriptional regulation of KSHV latency promoter and latent gene expression, the current study adds to the complexity that though LANA-1 (latency associated nuclear antigen) is utilizing COX-2/PGE2 as critical factors for its transcriptional regulation, it is the v-FLIP/K13 gene in the KSHV latency cluster that maintains continuous COX-2/PGE2 levels in the infected cells. We demonstrate that COX-2 inhibition, via its chemical inhibitors (NS-398 or celecoxib), reduced v-FLIP/K13-mediated NF-κB induction, and extracellular matrix (ECM) interaction-mediated signaling, mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD) levels, and subsequently downregulated detachment-induced apoptosis (anoikis) resistance. vFLIP expression mediated the secretion of cytokines, and spindle cell differentiation activated the phosphorylation of p38, RSK, FAK, Src, Akt and Rac1-GTPase. The COX-2 inhibition in v-FLIP/K13-HMVECs reduced inflammation and invasion/metastasis-related genes, along with reduced anchorage-independent colony formation via modulating ‘extrinsic' as well as ‘intrinsic' cell death pathways. COX-2 blockade in v-FLIP/K13-HMVEC cells drastically augmented cell death induced by removal of essential growth/survival factors secreted in the microenvironment. Transformed cells obtained from anchorage-independent colonies of COX-2 inhibitor-treated v-FLIP/K13-HMVEC cells expressed lower levels of endothelial–mesenchymal transition genes such as slug, snail and twist, and higher expression of the tumor-suppressor gene, E-cadherin. Taken together, our study provides strong evidences that FDA-approved COX-2 inhibitors have great potential in blocking tumorigenic events linked to KSHV's oncogenic protein v-FLIP/K13.
登录
查看更多内容
影响因子：
14.5
作者：
Cesarman, E;Knowles, DM
通讯作者：
Knowles, DM
影响因子：
4
作者：
Efklidou, Sofia;Bailey, Ranbir;Collins, Mary K.
通讯作者：
Collins, Mary K.
影响因子：
8
作者：
Jiang, XH;Lam, SK;Wong, BCY
通讯作者：
Wong, BCY
影响因子：
16
作者：
Cheng, EHYA;Wei, MC;Korsmeyer, SJ
通讯作者：
Korsmeyer, SJ
影响因子：
8
作者：
He, Q.;Luo, X.;Sheikh, M. S.
通讯作者：
Sheikh, M. S.