Skip to main content
  • Meeting abstracts
  • Open access
  • Published:

KSHV-mediated ROS induction defines novel therapeutic targets in Kaposi's sarcoma

Background

Kaposi’s sarcoma herpesvirus (KSHV) is the etiological agent of Kaposi’s sarcoma (KS). Understanding the interplay of viral and host factors in KS carcinogenesis is critical for the rational development of new therapies. Reactive oxygen species (ROS) have a recognized broad function in oncogenesis mediated by signaling cascades leading to the Rac1 activation of NADPH oxidases (Nox) [1]. ROS play a role in cell cycle regulation and angiogenesis, yet the specific molecular events linking ROS and these cancer hallmarks are still elusive. KSHV encodes a constitutively active G protein-coupled receptor (vGPCR) [2], which triggers KS-like sarcomagenesis via Rac1 [3]. It has been shown that Rac1-activated mutant induces tumors resembling Kaposi’s sarcoma by a ROS-mediated mechanism in transgenic mice [4, 5]. Moreover, Rac1 is overexpressed in AIDS-KS lesions and in KSHV-infected mECK36 tumors, pointing to a role for KSHV-induced Rac1-mediated production of ROS in KS pathogenesis [5]. The current study explored the induction of oxidative stress pathways in the KSHV-induced mouse model mECK36.

Results

vGPCR expression led to the upregulation of the c-sis/PDGFB oncogene in a dose-dependent manner in mECK36. PDGFB upregulation was dependent on Rac1 and ROS since it was suppressed by the Rac1 inhibitor EHT1864 and the ROS scavenger N-acetyl cysteine (NAC). PDGF activated oxidative signaling in a Rac/Nox/ROS-dependent manner in latently infected cells, leading to the upregulation of important genes for proliferation and angiogenesis, such as c-Myc and VEGFA through the activation of the STAT3 transcription factor. Treatment with antioxidant NAC and PDGF receptor inhibitors (imatinib and sunitinib) proved effective in inhibiting KSHV-induced tumorigenesis in the mECK36 mouse model.

Conclusions

Our results show a novel KSHV-driven oncogenic mechanism mediated by PDGF-B, whereby KSHV infection induces and exploits ROS production. ROS can be targeted therapeutically by using the NAC antioxidant or FDA-approved PDGF receptors inhibitors. Imatinib clinical responses in AIDS-KS could be due to PDGF-receptor inhibition of ROS production and warrant further clinical trials and molecular exploration of these new molecular therapeutic and prevention targets in AIDS-KS.

References

  1. Leto TL, Morand S, Hurt D, Ueyama T: Targeting and regulation of reactive oxygen species generation by Nox family NADPH oxidases. Antioxid Redox Signal. 2009, 11 (10): 2607-2619. 10.1089/ars.2009.2637.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Bais C, Santomasso B, Coso O, Arvanitakis L, Raaka EG, Gutkind JS, Asch AS, Cesarman E, Gershengorn MC, Mesri EA: G-protein-coupled receptor of Kaposi's sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator. Nature. 1998, 391 (6662): 86-89. 10.1038/34193.

    Article  CAS  PubMed  Google Scholar 

  3. Montaner S, Sodhi A, Servitja JM, Ramsdell AK, Barac A, Sawai ET, Gutkind JS: The small GTPase Rac1 links the Kaposi sarcoma-associated herpesvirus vGPCR to cytokine secretion and paracrine neoplasia. Blood. 2004, 104 (9): 2903-2911. 10.1182/blood-2003-12-4436.

    Article  CAS  PubMed  Google Scholar 

  4. Mutlu AD, Cavallin LE, Vincent L, Chiozzini C, Eroles P, Duran EM, Asgari Z, Hooper AT, La Perle KM, Hilsher C, Gao SJ, Dittmer DP, Rafii S, Mesri EA: In vivo-restricted and reversible malignancy induced by human herpesvirus-8 KSHV: a cell and animal model of virally induced Kaposi’s sarcoma. Cancer Cell. 2007, 11 (3): 245-258. 10.1016/j.ccr.2007.01.015.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. 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. 106 (21): 8683-8688. 10.1073/pnas.0812688106.

Download references

Acknowledgements

This article has been published as part of Infectious Agents and Cancer Volume 5 Supplement 1, 2010: Proceedings of the 12th International Conference on Malignancies in AIDS and Other Acquired Immunodeficiencies (ICMAOI).The full contents of the supplement are available online at http://www.biomedcentral.com/1750-9378/5?issue=S1.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Lucas E Cavallin.

Rights and permissions

Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and permissions

About this article

Cite this article

Cavallin, L.E., Ma, Q., Goldschmidt-Clermont, P. et al. KSHV-mediated ROS induction defines novel therapeutic targets in Kaposi's sarcoma. Infect Agents Cancer 5 (Suppl 1), A49 (2010). https://doi.org/10.1186/1750-9378-5-S1-A49

Download citation

  • Published:

  • DOI: https://doi.org/10.1186/1750-9378-5-S1-A49

Keywords