u-0126 and Sarcoma--Kaposi

Kaposi's sarcoma-associated herpesvirus (KSHV) establishes a latent infection in the host following an acute infection. Reactivation from latency contributes to the development of KSHV-induced malignancies, which include Kaposi's sarcoma (KS), the most common cancer in untreated AIDS patients, primary effusion lymphoma and multicentric Castleman's disease. However, the physiological cues that trigger KSHV reactivation remain unclear. Here, we show that the reactive oxygen species (ROS) hydrogen peroxide (H₂O₂) induces KSHV reactivation from latency through both autocrine and paracrine signaling. Furthermore, KSHV spontaneous lytic replication, and KSHV reactivation from latency induced by oxidative stress, hypoxia, and proinflammatory and proangiogenic cytokines are mediated by H₂O₂. Mechanistically, H₂O₂ induction of KSHV reactivation depends on the activation of mitogen-activated protein kinase ERK1/2, JNK, and p38 pathways. Significantly, H₂O₂ scavengers N-acetyl-L-cysteine (NAC), catalase and glutathione inhibit KSHV lytic replication in culture. In a mouse model of KSHV-induced lymphoma, NAC effectively inhibits KSHV lytic replication and significantly prolongs the lifespan of the mice. These results directly relate KSHV reactivation to oxidative stress and inflammation, which are physiological hallmarks of KS patients. The discovery of this novel mechanism of KSHV reactivation indicates that antioxidants and anti-inflammation drugs could be promising preventive and therapeutic agents for effectively targeting KSHV replication and KSHV-related malignancies.

Topics: Acetylcysteine; Animals; Blotting, Western; Butadienes; Catalase; Cell Line; Fluorescent Antibody Technique; Glutathione; HEK293 Cells; Herpesviridae Infections; Herpesvirus 8, Human; Humans; Hydrogen Peroxide; Imidazoles; JNK Mitogen-Activated Protein Kinases; Male; Mice; Mice, Inbred NOD; Mice, SCID; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Nitriles; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Pyridines; Reactive Oxygen Species; Reverse Transcriptase Polymerase Chain Reaction; Sarcoma, Kaposi; Signal Transduction; Virus Activation; Virus Latency; Virus Replication

Human herpesvirus-8 (HHV-8/KSHV) is etiologically associated with Kaposi's sarcoma (KS) and other tumors. Constitutive activation of the mitogen-activated protein kinase (MAPK) signaling pathway has been associated with a variety of tumors, including AIDS-related KS. The oncoprotein Raf is situated at a pivotal position in regulating the MAPK pathway. Hence, we analysed the effect of oncoprotein Raf on HHV-8 infectious entry into target cells. Here we report Raf expression to significantly enhance HHV-8 infection of target cells. These findings implicate a role for Raf not only in the infectious entry of HHV-8 but also in modulating KS pathogenesis.

Topics: AIDS-Related Opportunistic Infections; Blotting, Western; Butadienes; Cell Line; Enzyme Activation; Enzyme Inhibitors; Epidermal Growth Factor; Estradiol; Green Fluorescent Proteins; Heparin-binding EGF-like Growth Factor; Herpesviridae Infections; Herpesvirus 8, Human; Humans; Intercellular Signaling Peptides and Proteins; Luminescent Proteins; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Nitriles; Proto-Oncogene Proteins c-raf; Receptors, Estrogen; Recombinant Fusion Proteins; Sarcoma, Kaposi; Signal Transduction; Vascular Endothelial Growth Factor A