Antitumorigenesis of antioxidants in a transgenic Rac1 model of Kaposi's sarcoma
Open accessAbstract
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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In the Kaposi's sarcoma model, antioxidant treatment was associated with reduced Akt and HIF activities in tumors.
“In this case, treatment was associated with reduced Akt and HIF activities in tumors71.”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [71]
Antioxidants inhibited tumor growth in a mouse model of Kaposi's sarcoma.
“Similarly, antioxidants inhibited tumor growth in a mouse model of Kaposi’s sarcoma.”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [71]
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- Authors
- Ma, Q., Cavallin, L. E., Yan, B., Zhu, S., Duran, E. M., Wang, H., Hale, L. P., Dong, C., Cesarman, E., Mesri, E. A., & Goldschmidt-Clermont, P. J.
- Affiliations
- University of Miami (US)
- Virginia Commonwealth University Medical Center (US)
- University of North Carolina at Chapel Hill (US)
- Duke Medical Center (US)
- Cornell University (US)
- Vascular Biology Institute,
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-05-26
- Volume
- 106
- Issue
- 21
- Pages
- 8683-8688
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2679580
- OpenAlex
- W2041499308
- Cited by
- 105
- References
- 40
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2023: 4 · 2022: 4 · 2021: 3 · 2020: 7 · 2019: 6 · 2018: 4 · 2017: 7 · 2016: 6 · 2015: 10 · 2014: 16 · 2013: 5 · 2012: 5
- FWCI
- 4.25
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- University of Miami
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL071536, HL71536-08)
- National Cancer Institute (CA 75918, R01CA075918)
- National Institute of Allergy and Infectious Diseases (P30AI073961)
- Topics
- Health Sciences › Medicine › Oncology › Viral-associated cancers and disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- Kaposi's sarcoma, Rac1, reactive oxygen species, oxidative stress, Kaposi's sarcoma-associated herpesvirus, N-acetylcysteine, angiogenesis, Akt signaling, hypoxia-inducible factor-1α, transgenic mouse model, HIV-associated malignancies, inflammation-related cancer, chemoprevention, NADPH oxidase
- MeSH terms
- Acquired Immunodeficiency Syndrome, Animals, Antioxidants, Cell Transformation, Neoplastic, Disease Models, Animal, Enzyme Activation, Humans, Mice, Inbred C57BL, Mice, Transgenic, Neovascularization, Pathologic, Sarcoma, Kaposi, Transcription, Genetic, Tumor Cells, Cultured, Gene Expression Regulation, Neoplastic, Reactive Oxygen Species, rac1 GTP-Binding Protein, Gene Expression Profiling, Proto-Oncogene Proteins c-akt, Mice
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