Bay 11-7082 inhibits transcription factor NF-kappa B and induces apoptosis of HTLV-I-infected T-cell lines and primary adult T-cell leukemia cells

Abstract

Human T-cell leukemia virus type I (HTLV-I IntroductionAdult T-cell leukemia (ATL) is an aggressive malignancy of CD4 ϩ T cells, and its development is closely associated with human T-cell leukemia virus type I (HTLV-I) infection. [1][2][3] In vitro, HTLV-I transforms primary human CD4 ϩ T cells in interleukin-2 (IL-2)-dependent and IL-2-independent manners. Although the mechanism of transformation and leukemogenesis is not fully elucidated, there is evidence to suggest that the viral Tax protein plays a crucial role in these processes. For instance, like HTLV-I, Tax immortalizes primary human CD4 ϩ T cells in vitro and transforms rat fibroblast cell lines. 4,5 In addition, Tax inhibits apoptosis induced by various stimuli in T-cell lines. 6 Tax activates viral gene expression through the binding sequence for cAMP response element binding protein (CREB)/ activating transcription factor (ATF) in the 21-bp repeats of the HTLV-I long terminal repeat (LTR). Tax has been shown to activate the expression of a number of cellular genes through several distinct transcription factors, such as NF-B/Rel, AP-1, and serum response factor. 7-9 The cellular genes induced by Tax include cytokines/chemokines (IL-1␣, IL-6, IL-8, tumor necrosis factor-␤, monocyte chemoattractant protein-1, granulocyte macrophage-colony stimulating factor, and granulocyte colonystimulating factor), their receptors (the ␣ chain of IL-2 receptor [IL-2R] and IL-15R), cell adhesion molecule (OX40), matrix metalloproteinase (MMP-9), apoptosis inhibitor (Bcl-x L ), and G1-cyclins (cyclin D1 and cyclin D2). 7,10-21 The transcriptional activation of cellular genes, including those listed above, by Tax is thought to contribute to deregulated proliferation of HTLV-Iinfected cells.Accumulating evidence suggests that activation of cellular genes by Tax through NF-B is a critical process in the transforming activity as well as the inhibition of apoptosis. For instance, a Tax mutant inactive for NF-B cannot immortalize primary human T cells in vitro. 22 NF-B2, a member of the IB protein family, abrogates the transformation of a rat fibroblast cell line by Tax. 5 Tax inhibits apoptosis induced by IL-2 withdrawal in mouse factor-dependent T-cell lines, and such inhibition correlates with the activation of NF-B and induction of the antiapoptotic gene Bcl-x L through the NF-B pathway. 23,24 In resting T cells, NF-B is sequestered in the cytoplasm in an inactive form by association with an inhibitory IB subunit. Activation of NF-B generally involves phosphorylation and degradation of IBs, followed by nuclear translocation of NF-B and subsequent activation of the genes containing NF-B binding sites. IBs are phosphorylated by a multisubunit IB kinase (IKK) complex, which is composed of 2 catalytic subunits, IKK␣ and IKK␤, and a noncatalytic subunit, IKK␥/NEMO. Tax Reprints: Naoki Mori, Department of Virology, Faculty of Medicine, University of the Ryukyus, 207, Uehara, Nishihara, Okinawa 903-0215, Japan; e-mail: n-mori@med.u-ryukyu.ac.jp.The publication costs of this ar...

Retracted: Overexpression of Aurora A by loss of CHFR gene expression increases the growth and survival of HTLV‐1‐infected T cells through enhanced NF‐κB activity

“…We reported previously that Bay 11-7082, an NF-jB inhibitor, blocked constitutive NF-jB activation and induced apoptosis of HTLV-1-infected T-cells. 40 Here, we found that treatment with Aurora kinase inhibitor suppressed constitutively activated NF-jB signaling in HTLV-1-infected T-cell lines. Knockdown of Aurora A reduced phosphorylation of IKKb, but not IKKa or IKKg (data not shown).…”

“…This is important because constitutively activated NF-jB signaling plays important roles in the growth and survival of HTLV-1-infected T cells. 36,40 Aurora A siRNA reduced phosphorylation of IKKb, but not that of IKKa and IKKg, without affecting Tax expression in HUT-102 cells (Fig. 3b and data not shown).…”

Transcriptional activation of survivin through the NF‐κB pathway by human T‐cell leukemia virus type I tax

“…[44][45][46] Inhibition of NF-kB signaling resulted in apoptosis and decreased Bcl-x L expression in HTLV-I-infected T-cell lines and primary ATL cells. 47 In our study, we investigated the relationship between HTLV-I and ATL with respect to the induction of resistance to apoptosis in T-cells mediated by HTLV-I Tax. As reported previously, 19 NF-kB nuclear translocation was stimulated in Tax-transfected CTLL-2 cells in the absence of IL-2.…”

Activation of NF-κB by the Human T Cell Leukemia Virus Type I Tax Oncoprotein Is Associated with Ubiquitin-dependent Relocalization of IκB Kinase

“…Tax activation of NF-B is required for immortalization of T lymphocytes (4). Further, pharmacologic inhibition of NF-B leads to apoptosis of HTLV-1 transformed T cell lines and ATL cells (5).…”