HIV-1-Tat Protein Activates Phosphatidylinositol 3-Kinase/ AKT-dependent Survival Pathways in Kaposi's Sarcoma Cells

Abstract

In this study we found that Tat protected vincristinetreated Kaposi's sarcoma cells from apoptosis and from down-regulation of several anti-apoptotic genes such as AKT-1, AKT-2, BCL2, BCL-XL, and insulin-like growth factor I and induced the de novo expression of the interleukin-3 gene. Moreover, we found that Tat enhanced phosphorylation of AKT and BAD proteins. The inhibition of phosphatidylinositol 3-kinase with two unrelated pharmacological inhibitors, wortmannin and LY294002, abrogated both the anti-apoptotic effect and the phosphorylation of AKT induced by Tat. After treatment with Tat, the AKT enzymatic activity showed a biphasic increase: an early activation (15 min), independent from protein synthesis; and a delayed activation (24 h), which was significantly decreased upon blockage of protein synthesis. Experiments with a function blocking antivascular endothelial cell growth factor receptor-2 antibody suggested that both the early and delayed AKT activation and the protection from apoptosis were triggered by the interaction of Tat with vascular endothelial cell growth factor receptor-2. Moreover, experiments with function-blocking antibodies directed against insulin-like growth factor I/insulin-like growth factor I receptor or interleukin-3 indicated their involvement in the delayed activation of AKT and their contribution to the anti-apoptotic effect of Tat on vincristine-treated Kaposi's sarcoma cells.

Remission from Kaposi's sarcoma on HAART is associated with suppression of HIV replication and is independent of protease inhibitor therapy

“…Uncontrolled HIV replication is associated with progression of HHV-8 malignancies (Nicholas et al, 1997;Brodt et al, 1998). As in previous studies, we found that suppression of HIV replication was crucial for controlling KS (Albini et al, 1995;Boshoff et al, 1995;Nicholas et al, 1997;Barillari and Ensoli, 2002;Deregibus et al, 2002).…”

“…It stimulates the growth of KS lesions by stimulating the proliferation of spindle cells, activating cytokine genes (e.g. IL-6) and inhibiting IFN-g-mediated apoptosis (Boshoff et al, 1995;Nicholas et al, 1997;Deregibus et al, 2002). The Tat gene has a direct angiogenic effect by interacting with several receptors, and also enhances HHV-8 infectivity (Albini et al, 1995;Aoki and Tosato, 2004).…”

The interaction between KDR and interleukin-3 receptor (IL-3R) beta common modulates tumor neovascularization

“…With regard to this, we have recently shown that the inflammatory cytokine interleukin-3 (IL-3) (Dentelli et al, 1999) is released into the microenvironment of breast cancer tissues (Dentelli et al, 2004) and, consistent with the original observation that activated T-lymphocytes are the main cellular source of IL-3 (Wimperis et al, 1989), we also found that in noninvasive breast cancer tissues a subset of tumorinfiltrating CD25/CD4/CD5 þ T cells expressed IL-3 (Dentelli et al, 1999). Moreover, we also previously showed that IL-3 is secreted by tat-expressing cells (Deregibus et al, 2002), and that, besides tumorinfiltrating lymphocytes, tumor-derived ECs also represent an important source of IL-3 (Bussolati et al, 2003).…”

“…Thus, despite considerable progress in understanding the intracellular mechanisms mediating the action of VEGF in the endothelium (Tanimoto et al, 2002;Thuringer et al, 2002), important areas of VEGF receptor signal transduction remain to be elucidated. The observation that IL-3, as VEGF, is released into the tumor microenvironment (Deregibus et al, 2002;Bussolati et al, 2003;Dentelli et al, 2004) led us to investigate if and how IL-3 by itself or in cooperation with VEGF may contribute to tumor neoangiogenesis.…”

Clionosterol and Ethyl Cholestan-22-enol Isolated from the Rhizome of <i>Polygala tenuifolia</i> Inhibit Phosphatidylinositol 3-Kinase/Akt Pathway

“…2) The PI3K/Akt cell survival pathway is particularly activated by several key human pathogenic viruses such as human papillomavirus (HPV), 3) and human immunodeficiency virus type 1 (HIV-1). 4) This virus-induced activation of PI3K/Akt pathway involves specific viral proteins such as E6/E7 of HPV, NS5A of hepatitis C virus (HCV), Tax of human T-tropic virus (HTLV) and Tat of HIV-1. Of them, the expression of Tat appears to inactivate a negative regulator of the PI3K/Akt pathway, called PTEN.…”