The small GTPase Rac1 links the Kaposi sarcoma-associated herpesvirus vGPCR to cytokine secretion and paracrine neoplasia.
Kaposi sarcoma (KS) is a multifocal angioproliferative neoplasm strictly dependent on angiogenic growth factors and cytokines and invariably associated with infection by the Kaposi sarcoma-associated herpesvirus (KSHV or HHV8). A G protein-coupled receptor encoded by KSHV (vGPCR) is able to initiate KS-like tumors when targeted to the vascular endothelium of mice. Analogous to human KS, vGPCR sarcomagenesis involves the paracrine secretion of angiogenic growth factors and proinflammatory molecules from vGPCR-expressing cells. Here we demonstrate that vGPCR up-regulates expression and secretion of critical KS cytokines by stimulating key transcription factors, including nuclear factor-kappaB (NF-kappaB), activator protein-1 (AP-1), and nuclear factor of activated T cells (NFAT), through the activation of the small G protein Rac1. Inhibition of Rac1 blocked vGPCR-induced transcription and secretion of KS cytokines, including interleukin-6 (IL-6), IL-8, and growth-regulated oncogene alpha (GROalpha), in vitro and reduced vGPCR tumorigenesis in vivo. Moreover, endothelial-specific infection with the constitutively active Rac1QL induced vascular lesions in mice that were remarkably similar to early vGPCR experimental lesions. These results identify Rac1 as a key mediator of vGPCR paracrine neoplasia, suggesting that this small G protein and its downstream effectors may represent suitable therapeutic targets for the treatment of KS.
Montaner
Silvia
S
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Dr, Bldg 30, Rm 212, Bethesda, MD 20892-4330, USA.
Sodhi
Akrit
A
Servitja
Joan-Marc
JM
Ramsdell
Amanda K
AK
Barac
Ana
A
Sawai
Earl T
ET
Gutkind
J Silvio
JS
D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000473:pathology / Q000821:virology; D019288:Herpesvirus 8, Human / Q000737:chemistry / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D019899:Paracrine Communication; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000502:physiology*; D012514:Sarcoma, Kaposi / Q000209:etiology* / Q000473:pathology / Q000821:virology; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000235:genetics; D014764:Viral Proteins / Q000235:genetics / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism / Q000502:physiology*
D016207:Cytokines; D043562:Receptors, G-Protein-Coupled; D014157:Transcription Factors; D014764:Viral Proteins; D020830:rac1 GTP-Binding Protein