PI3Kγ mediates kaposi's sarcoma-associated herpesvirus vGPCR-induced sarcomagenesis

Cancer Cell. 2011 Jun 14;19(6):805-13. doi: 10.1016/j.ccr.2011.05.005.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Transformation, Viral*
  • Class Ib Phosphatidylinositol 3-Kinase / physiology*
  • Humans
  • Mice
  • Proto-Oncogene Proteins c-akt / physiology
  • Receptors, G-Protein-Coupled / physiology*
  • Sarcoma, Kaposi / etiology*
  • TOR Serine-Threonine Kinases / physiology
  • Viral Proteins / physiology*

Substances

  • Receptors, G-Protein-Coupled
  • Viral Proteins
  • TOR Serine-Threonine Kinases
  • Class Ib Phosphatidylinositol 3-Kinase
  • PIK3CG protein, human
  • Pik3cg protein, mouse
  • Proto-Oncogene Proteins c-akt