pi103 and Skin-Neoplasms

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

The phosphatidyl inositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway has been shown to be involved in the development of melanoma. PI-103 is a kinase inhibitor blocking PI3K class IA and mTOR complex 1 and 2. Here, we studied the effect of targeting the PI3K/mTORC1/mTORC2 pathway by PI-103 and rapamycin in melanoma cells and in a melanoma mouse model. Dual targeting of PI3K and mTOR by PI-103 induced apoptosis and cell-cycle arrest, and inhibited viability of melanoma cells in vitro. Combined treatment with PI-103 and the prototypic mTORC1 inhibitor rapamycin led to the synergistic suppression of AKT and ribosomal S6 protein phosphorylation and to the induction of apoptosis. In vivo, PI-103 and rapamycin displayed only modest single-agent activity, but the combination significantly reduced the tumor growth compared with both single agents. These data show that blocking the PI3K/mTORC1/mTORC2 pathway using the combination of two distinct small-molecule inhibitors ("vertical inhibition") leads to superior efficacy against malignant melanoma in vitro and in vivo.

Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Disease Models, Animal; Enzyme Inhibitors; Female; Furans; Humans; In Vitro Techniques; Mechanistic Target of Rapamycin Complex 1; Melanoma; Mice; Mice, Nude; Multiprotein Complexes; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proteins; Pyridines; Pyrimidines; Signal Transduction; Sirolimus; Skin Neoplasms; TOR Serine-Threonine Kinases; Trans-Activators; Transcription Factors; Transplantation, Heterologous