title: A role for virally induced reactive oxygen species in Kaposi's sarcoma herpesvirus tumorigenesis.
abstract: OBJECTIVE
  Kaposi's sarcoma (KS), caused by the Kaposi's sarcoma herpesvirus (KSHV), is an AIDS-associated cancer characterized by angiogenesis and proliferation of spindle cells. Rac1-activated reactive oxygen species (ROS) production has been implicated in KS tumorigenesis. We used an animal model of KSHV-induced Kaposi's sarcomagenesis (mECK36) to study the role of ROS in KS and the efficacy of N-acetyl l-cysteine (NAC) in inhibiting or preventing KS.
  
  
  RESULTS
  Signaling by the KSHV early lytic gene viral G protein-coupled receptor (vGPCR) activated ROS production in mECK36 cells via a Rac1-NADPH oxidase pathway. Induction of the lytic cycle in KSHV-infected KS spindle cells upregulated ROS along with upregulation of vGPCR expression. We also found that expression of the major latent transcript in 293 cells increased ROS levels. ROS scavenging with NAC halted mECK36 tumor growth in a KSHV-specific manner. NAC inhibited KSHV latent gene expression as well as tumor angiogenesis and lymphangiogenesis. These effects correlated with the reduction of vascular endothelial growth factor (VEGF), c-myc, and cyclin D1, and could be explained on the basis of inhibition of STAT3 tyrosine phosphorylation. NAC prevented mECK36 de novo tumor formation. Molecular analysis of NAC-resistant tumors revealed a strong upregulation of Rac1 and p40(PHOX).
  
  
  CONCLUSIONS
  Our results demonstrate that ROS-induction by KSHV plays a causal role in KS oncogenesis by promoting proliferation and angiogenesis. Our results show that both ROS and their molecular sources can be targeted therapeutically using NAC or other Food and Drug Administration (FDA)-approved inhibitors for prevention and treatment of AIDS-KS.
authors: Viral Oncology Program, Department of Microbiology and Immunology, Sylvester Comprehensive Cancer Center and Center for AIDS Research, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.
authors: Qi
authors: Q
authors: Ma
authors: Lucas E
authors: LE
authors: Cavallin
authors: Howard J
authors: HJ
authors: Leung
authors: Chiara
authors: C
authors: Chiozzini
authors: Pascal J
authors: PJ
authors: Goldschmidt-Clermont
authors: Enrique A
authors: EA
authors: Mesri
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology / Q000627:therapeutic use; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism*; D016166:Free Radical Scavengers / Q000494:pharmacology / Q000627:therapeutic use; D015870:Gene Expression / Q000187:drug effects; D057809:HEK293 Cells; D019288:Herpesvirus 8, Human / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D009479:Neuropeptides / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D012514:Sarcoma, Kaposi / Q000473:pathology / Q000517:prevention & control / Q000821:virology*; D014158:Transcription, Genetic / Q000187:drug effects; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein
chemical_list: D020533:Angiogenesis Inhibitors; D000998:Antiviral Agents; D016166:Free Radical Scavengers; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D017382:Reactive Oxygen Species; D043562:Receptors, G-Protein-Coupled; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D014764:Viral Proteins; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D000111:Acetylcysteine