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Antitumorigenesis of antioxidants in a transgenic Rac1 model of Kaposi's sarcoma.

Publication ,  Journal Article
Ma, Q; Cavallin, LE; Yan, B; Zhu, S; Duran, EM; Wang, H; Hale, LP; Dong, C; Cesarman, E; Mesri, EA; Goldschmidt-Clermont, PJ
Published in: Proc Natl Acad Sci U S A
May 26, 2009

Kaposi's sarcoma (KS) is the major AIDS-associated malignancy. It is characterized by the proliferation of spindle cells, inflammatory infiltrate, and aberrant angiogenesis caused by Kaposi's sarcoma herpesvirus (KSHV) infection. Small GTPase Rac1, an inflammatory signaling mediator triggering reactive oxygen species (ROS) production by NADPH-oxidases, is implicated in carcinogenesis and tumor angiogenesis. Here, we show that expression of a constitutively active Rac1 (RacCA) driven by the alpha-smooth muscle actin promoter in transgenic mice is sufficient to cause KS-like tumors through mechanisms involving ROS-driven proliferation, up-regulation of AKT signaling, and hypoxia-inducible factor 1-alpha-related angiogenesis. RacCA-induced tumors expressed KS phenotypic markers; displayed remarkable transcriptome overlap with KS lesions; and were, like KS, associated with male gender. The ROS scavenging agent N-acetyl-cysteine inhibited angiogenesis and completely abrogated transgenic RacCA tumor formation, indicating a causal role of ROS in tumorigenesis. Consistent with a pathogenic role in KS, immunohistochemical analysis revealed that Rac1 is overexpressed in KSHV(+) spindle cells of AIDS-KS biopsies. Our results demonstrate the direct oncogenicity of Rac1 and ROS and their contribution to a KS-like malignant phenotype, further underscoring the carcinogenic potential of oxidative stress in the context of chronic infection and inflammation. They define the RacCA transgenic mouse as a model suitable for studying the role of oxidative stress in the pathogenesis and therapy of KS, with relevance to other inflammation-related malignancies. Our findings suggest host and viral genes triggering Rac1 or ROS production as key determinants of KS onset and potential KS chemopreventive or therapeutic targets.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

May 26, 2009

Volume

106

Issue

21

Start / End Page

8683 / 8688

Location

United States

Related Subject Headings

  • rac1 GTP-Binding Protein
  • Tumor Cells, Cultured
  • Transcription, Genetic
  • Sarcoma, Kaposi
  • Reactive Oxygen Species
  • Proto-Oncogene Proteins c-akt
  • Neovascularization, Pathologic
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice
 

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Ma, Q., Cavallin, L. E., Yan, B., Zhu, S., Duran, E. M., Wang, H., … Goldschmidt-Clermont, P. J. (2009). Antitumorigenesis of antioxidants in a transgenic Rac1 model of Kaposi's sarcoma. Proc Natl Acad Sci U S A, 106(21), 8683–8688. https://doi.org/10.1073/pnas.0812688106
Ma, Qi, Lucas E. Cavallin, Bin Yan, Shoukang Zhu, Elda Margarita Duran, Huili Wang, Laura P. Hale, et al. “Antitumorigenesis of antioxidants in a transgenic Rac1 model of Kaposi's sarcoma.Proc Natl Acad Sci U S A 106, no. 21 (May 26, 2009): 8683–88. https://doi.org/10.1073/pnas.0812688106.
Ma Q, Cavallin LE, Yan B, Zhu S, Duran EM, Wang H, et al. Antitumorigenesis of antioxidants in a transgenic Rac1 model of Kaposi's sarcoma. Proc Natl Acad Sci U S A. 2009 May 26;106(21):8683–8.
Ma, Qi, et al. “Antitumorigenesis of antioxidants in a transgenic Rac1 model of Kaposi's sarcoma.Proc Natl Acad Sci U S A, vol. 106, no. 21, May 2009, pp. 8683–88. Pubmed, doi:10.1073/pnas.0812688106.
Ma Q, Cavallin LE, Yan B, Zhu S, Duran EM, Wang H, Hale LP, Dong C, Cesarman E, Mesri EA, Goldschmidt-Clermont PJ. Antitumorigenesis of antioxidants in a transgenic Rac1 model of Kaposi's sarcoma. Proc Natl Acad Sci U S A. 2009 May 26;106(21):8683–8688.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

May 26, 2009

Volume

106

Issue

21

Start / End Page

8683 / 8688

Location

United States

Related Subject Headings

  • rac1 GTP-Binding Protein
  • Tumor Cells, Cultured
  • Transcription, Genetic
  • Sarcoma, Kaposi
  • Reactive Oxygen Species
  • Proto-Oncogene Proteins c-akt
  • Neovascularization, Pathologic
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice