title: PI3Kγ mediates kaposi's sarcoma-associated herpesvirus vGPCR-induced sarcomagenesis.
abstract: Angioproliferative tumors induced by the Kaposi's sarcoma-associated herpesvirus (KSHV) have been successfully treated with rapamycin, which provided direct evidence of the clinical activity of mTOR inhibitors in human malignancies. However, prolonged mTOR inhibition may raise concerns in immunocompromised patients, including AIDS-Kaposi's sarcoma (KS). Here, we explored whether KSHV oncogenes deploy cell type-specific signaling pathways activating mTOR, which could be exploited to halt KS development while minimizing immune suppressive effects. We found that PI3Kγ, a PI3K isoform exhibiting restricted tissue distribution, is strictly required for signaling from the KSHV-encoded vGPCR oncogene to Akt/mTOR. Indeed, by using an endothelial-specific gene delivery system modeling KS development, we provide genetic and pharmacological evidence that PI3Kγ may represent a suitable molecular target for therapeutic intervention in KS.
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Martin
authors.forename: Rebeca
authors.initials: R
authors.lastname: Galisteo
authors.forename: Alfredo A
authors.initials: AA
authors.lastname: Molinolo
authors.forename: Reinhard
authors.initials: R
authors.lastname: Wetzker
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
authors.forename: J Silvio
authors.initials: JS
authors.lastname: Gutkind
mesh_terms: D000818:Animals; D002460:Cell Line; D002472:Cell Transformation, Viral; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000502:physiology*; D006801:Humans; D051379:Mice; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D012514:Sarcoma, Kaposi / Q000209:etiology*; D058570:TOR Serine-Threonine Kinases / Q000502:physiology; D014764:Viral Proteins / Q000502:physiology*
chemical_list: D043562:Receptors, G-Protein-Coupled; D014764:Viral Proteins; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546760:PIK3CG protein, human; C546764:Pik3cg protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases