A role for virally induced reactive oxygen species in kaposi's sarcoma herpesvirus tumorigenesis

Qi Ma, Lucas E. Cavallin, Howard J. Leung, Chiara Chiozzini, Pascal Goldschmidt-Clermont, Enrique A Mesri

Research output: Contribution to journalArticle

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Abstract

Aims: 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 p40PHOX. Innovation and Conclusion: 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.

Original languageEnglish
Pages (from-to)80-90
Number of pages11
JournalAntioxidants and Redox Signaling
Volume18
Issue number1
DOIs
StatePublished - Jan 1 2013

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Kaposi's Sarcoma
Herpesviridae
Acetylcysteine
Reactive Oxygen Species
Carcinogenesis
Tumors
Cysteine
G-Protein-Coupled Receptors
Viral Proteins
Phosphorylation
Neoplasms
NADPH Oxidase
Cyclin D1
Scavenging
Gene expression
Acquired Immunodeficiency Syndrome
Vascular Endothelial Growth Factor A
Up-Regulation
Tyrosine
Animals

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Physiology
  • Clinical Biochemistry

Cite this

A role for virally induced reactive oxygen species in kaposi's sarcoma herpesvirus tumorigenesis. / Ma, Qi; Cavallin, Lucas E.; Leung, Howard J.; Chiozzini, Chiara; Goldschmidt-Clermont, Pascal; Mesri, Enrique A.

In: Antioxidants and Redox Signaling, Vol. 18, No. 1, 01.01.2013, p. 80-90.

Research output: Contribution to journalArticle

Ma, Qi ; Cavallin, Lucas E. ; Leung, Howard J. ; Chiozzini, Chiara ; Goldschmidt-Clermont, Pascal ; Mesri, Enrique A. / A role for virally induced reactive oxygen species in kaposi's sarcoma herpesvirus tumorigenesis. In: Antioxidants and Redox Signaling. 2013 ; Vol. 18, No. 1. pp. 80-90.
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