pi103 and Sarcoma--Kaposi

Kaposi Sarcoma (KS) are opportunistic tumors, associated with human herpes virus 8 (HHV8) infection. KS development is highly favored by immune-depression and remains the second most frequent tumor in acquired immune deficiency syndrome patients. Although it has been shown that experimental expression of the HHV8 G-protein-coupled receptor (vGPCR) in the endothelial compartment is alone sufficient to recapitulate the formation and progression of KS-like lesions, its functional effects on endothelial homeostasis are not fully understood. Here we show that vGPCR expression in endothelial cells induces an increase in paracellular permeability both in vivo and in vitro. By using pharmacological inhibitors and small interference RNA-based knockdown, we demonstrate an essential role for the PI(3)Kinase-γ/Rac nexus in vGPCR-mediated permeability. This was further accompanied by dramatic remodeling of VE-cadherin-dependent cell-cell junctions. Importantly, this in vitro vGPCR-initiated signaling signature was observed in a large panel of human KS. Altogether, our results support the hypothesis that endothelial vGPCR signaling is co-opted in KS, and unveil new key cellular targets for therapeutic intervention.

Topics: Acquired Immunodeficiency Syndrome; Androstadienes; Animals; Antigens, CD; Cadherins; Capillary Permeability; Cell Line; Chromones; Cinnamates; Endothelial Cells; Enzyme Inhibitors; Female; Furans; Herpesvirus 8, Human; Humans; Indoles; Intercellular Junctions; Mice; Mice, Nude; Morpholines; Phosphatidylinositol 3-Kinases; Pyridines; Pyrimidines; Quinoxalines; Receptors, Chemokine; RNA, Small Interfering; Sarcoma, Kaposi; Skin; Skin Neoplasms; Sulfonamides; Thiazolidinediones; Wortmannin

Rapamycin (or sirolimus), the prototypical inhibitor of the mammalian target of rapamycin (mTOR) and an immunosuppressant used for the prevention of renal transplant rejection, has recently emerged as an effective treatment for Kaposi's sarcoma (KS), an enigmatic vascular tumor and a model for pathologic angiogenesis. Indeed, recent work supports a role for mTOR as a central player in the transformation of endothelial cells by the KS-associated herpesvirus-encoded G protein-coupled receptor (vGPCR), the viral oncogene believed to be responsible for causing KS. However, emerging evidence that rapamycin may transiently promote the activation of Akt may limit its use as an anti-KS therapy. Here, we show that activation of Akt in endothelial cells expressing vGPCR is augmented by treatment with rapamycin, resulting in the up-regulation of several Akt proliferative and survival pathways. However, use of a novel dual phosphatidylinositol 3-kinase alpha (PI3Kalpha)/mTOR inhibitor, PI-103, effectively and independently blocked activation of both PI3K and mTOR in vGPCR-expressing endothelial cells. This resulted in more effective inhibition of endothelial cell proliferation and survival in vitro and tumor growth in vivo. Our results suggest that PI-103 may be an effective therapeutic option for the treatment of patients with KS. Moreover, as KS may serve as a model for pathologic angiogenesis, our results further provide the basis for the early assessment of PI-103 as an antiangiogenic chemotherapeutic.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Apoptosis; Cell Line; Cell Proliferation; Endothelial Cells; Furans; Immunosuppressive Agents; Mice; Neoplasm Transplantation; Phosphoinositide-3 Kinase Inhibitors; Protein Kinases; Proto-Oncogene Proteins c-akt; Pyridines; Pyrimidines; Receptors, G-Protein-Coupled; Sarcoma, Kaposi; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Transplantation, Homologous