Akt plays a central role in sarcomagenesis induced by Kaposi's sarcoma herpesvirus-encoded G protein-coupled receptor.
We have recently engineered an in vivo endothelial cell-specific retroviral gene transfer system and found that a single Kaposi's sarcoma (KS)-associated herpesvirus/human herpesvirus 8 gene encoding a G protein-coupled receptor (vGPCR), is sufficient to induce KS-like tumors in mice. By using this system, we show here that the Akt signaling pathway plays a central role in vGPCR oncogenesis. Indeed, a constitutively active Akt was sufficient to induce benign hemangiomas in mice, whereas heterozyogosity for PTEN (the phosphatase and tension homologue deleted on chromosome 10), modestly enhancing basal Akt activity, dramatically enhanced vGPCR sarcomagenesis. Examination of KS biopsies from AIDS patients revealed active Akt as a prominent feature, supportive of a role for Akt in human Kaposi's sarcomagenesis. By using a vGPCR agonist-dependent mutant, we further establish constitutive activity as a requirement for vGPCR sarcomagenesis, validating targeted inhibition of key vGPCR signaling pathways as an approach for preventing its oncogenic potential. These observations prompted us to explore the efficacy of inhibiting Akt activation as a molecular approach to KS treatment. Pharmacological inhibition of the Akt pathway with the chemotherapeutic agent 7-hydroxystaurosporine prevented proliferation of vGPCR-expressing endothelial cells in vitro and inhibited their tumorigenic potential in vivo. Both were associated with a decrease in Akt activity. These results identify Akt as an essential player in vGPCR sarcomagenesis and demonstrate the therapeutic potential of drugs targeting this pathway in the treatment of KS.
Sodhi
Akrit
A
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
Montaner
Silvia
S
Patel
Vyomesh
V
Gómez-Román
José Javier
JJ
Li
Yi
Y
Sausville
Edward A
EA
Sawai
Earl T
ET
Gutkind
J Silvio
JS
D000818:Animals; D002461:Cell Line, Transformed; D019204:GTP-Binding Proteins / Q000378:metabolism*; D019288:Herpesvirus 8, Human / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D011956:Receptors, Cell Surface / Q000502:physiology*; D012514:Sarcoma, Kaposi / Q000209:etiology* / Q000473:pathology; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000494:pharmacology
D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; C054852:7-hydroxystaurosporine; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019204:GTP-Binding Proteins; D019311:Staurosporine