Hirochika Kawakami

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

Survivin, a unique member of the inhibitor of apoptosis protein family, is overexpressed in many cancers and considered to play an important role in oncogenesis. We previously reported the survivin expression profile in ATL, a CD4‐positive T‐cell malignancy caused by HTLV‐I. HTLV‐I Tax is thought to play an important role in immortalization of T cells. We have shown also that the expression of Tax protected the mouse T‐cell line CTLL‐2 against apoptosis induced by deprivation of IL‐2 and converted its growth from being IL‐2 dependent to being IL‐2 independent through the NF‐κB pathway. In our study, we demonstrate that constitutive expression of survivin was associated with resistance to apoptosis after IL‐2 deprivation in Tax‐expressing CTLL‐2 cells. Transient transfection assays showed that survivin promoter was transactivated by Tax, via the activation of NF‐κB. Pharmacological NF‐κB inhibition resulted in suppression of survivin expression and caused apoptosis of Tax‐expressing CTLL‐2 cells. Our findings suggest that activated NF‐κB signaling contributes directly to malignant progression of ATL by preventing apoptosis, acting through the prosurvival protein survivin.

Fucoidan extracted from Cladosiphon okamuranus Tokida induces apoptosis of human T-cell leukemia virus type 1-infected T-cell lines and primary adult T-cell leukemia cells.

Abstract: Adult T-cell leukemia (ATL) is caused by human T-cell leukemia virus type 1 (HTLV-1) and remains incurable. The highest endemic area of HTLV-1 carriers in Japan is located in Okinawa, and novel treatments are urgently needed in this area. We extracted fucoidan, a sulfated polysaccharide, from the brown seaweed Cladosiphon okamuranus Tokida cultivated in Okinawa, Japan and examined its tumor-suppression activity against ATL. Fucoidan significantly inhibited the growth of peripheral blood mononuclear cells of ATL patients and HTLV-1-infected T-cell lines but not that of normal peripheral blood mononuclear cells. Fucoidan induced apoptosis of HTLV-1-infected T-cell lines mediated through downregulation of cellular inhibitor of apoptosis protein-2 and survivin and G1 phase accumulation through the downregulation of cyclin D2, c-myc, and hyperphosphorylated form of the retinoblastoma tumor suppressor protein. Further analysis showed that fucoidan inactivated NF-κB and activator protein-1 and inhibited NF-κB-inducible chemokine, C-C chemokine ligand 5 (regulated on activation, normal T expressed and secreted) production, and homotypic cell-cell adhesion of HTLV-1-infected T-cell lines. In vivo use of fucoidan resulted in partial inhibition of growth of tumors of an HTLV-1-infected T-cell line transplanted subcutaneously in severe combined immune deficient mice. Our results indicate that fucoidan is a potentially useful therapeutic agent for patients with ATL.

Retracted: Curcumin (diferuloylmethane) inhibits constitutive active NF-κB, leading to suppression of cell growth of human T-cell leukemia virus type I-infected T-cell lines and primary adult T-cell leukemia cells

Retraction: The following article has been retracted through agreement between the first author and several coauthors, the journal Editor‐in‐Chief, Peter Lichter, and John Wiley & Sons, Ltd.: Tomita M, Kawakami H, Uchihara JN, Okudaira T, Masuda M, Takasu N, Matsuda T, Ohta T, Tanaka Y, Ohshiro K, Mori N. (2006). Curcumin (diferuloylmethane) inhibits constitutive activeNF‐kappaB, leading to suppression of cell growth of human T‐cell leukemia virus type I‐infected T‐cell lines and primary adult T‐cell leukemia cells. Int J Cancer; 118 (February (3)): 765‐772, published online on 16 AUG 2005 in Wiley Online Library (www.onlinelibrary.wiley.com). After an investigation the retraction has been agreed due to inappropriate duplication of images and overlap with other published work

Inhibition of constitutively active Jak-Stat pathway suppresses cell growth of human T-cell leukemia virus type 1-infected T-cell lines and primary adult T-cell leukemia cells

BackgroundHuman T-cell leukemia virus type 1 (HTLV-1), the etiologic agent for adult T-cell leukemia (ATL), induces cytokine-independent proliferation of T-cells, associated with the acquisition of constitutive activation of Janus kinases (Jak) and signal transducers and activators of transcription (Stat) proteins. Our purposes in this study were to determine whether activation of Jak-Stat pathway is responsible for the proliferation and survival of ATL cells, and to explore mechanisms by which inhibition of Jak-Stat pathway kills ATL cells.ResultsConstitutive activation of Stat3 and Stat5 was observed in HTLV-1-infected T-cell lines and primary ATL cells, but not in HTLV-1-negative T-cell lines. Using AG490, a Jak-specific inhibitor, we demonstrated that the activation of Stat3 and Stat5 was mediated by the constitutive phosphorylation of Jak proteins. AG490 inhibited the growth of HTLV-1-infected T-cell lines and primary ATL cells by inducing G1 cell-cycle arrest mediated by altering the expression of cyclin D2, Cdk4, p53, p21, Pim-1 and c-Myc, and by apoptosis mediated by the reduced expression of c-IAP2, XIAP, survivin and Bcl-2. Importantly, AG490 did not inhibit the growth of normal peripheral blood mononuclear cells.ConclusionOur results indicate that activation of Jak-Stat pathway is responsible for the proliferation and survival of ATL cells. Inhibition of this pathway may provide a new approach for the treatment of ATL.

Curcumin targets Akt cell survival signaling pathway in HTLV-I-infected T-cell lines

The Akt signaling pathway is important for survival and growth of cancer cells. In the present paper we show that the Akt signaling pathway is constitutively activated in human T‐cell leukemia virus type I (HTLV‐I)‐infected T‐cell lines and in primary adult T‐cell leukemia (ATL) cells. Curcumin, a natural compound present in turmeric, has been studied vigorously as a potent chemopreventive agent for cancer therapy because of its inhibitory effect on proliferation and induction of apoptosis in several tumor cell lines. We investigated the effect of curcumin on Akt activity in HTLV‐I‐infected T‐cell lines and primary ATL cells. Phosphorylated PDK1 is an activator of Akt by phosphorylating Akt. Curcumin reduced phosphorylation of PDK1 and inhibited constitutive activation of Akt. Curcumin activated glycogen synthase kinase (GSK)‐3β, a downstream target of Akt kinase, by inhibiting phosphorylation of this protein. Curcumin reduced the expression of cell cycle regulators, cyclin D1 and c‐Myc proteins, which are both degraded by activated GSK‐3β. Our results suggest that activation of the Akt signaling pathway plays an important role in ATL cell survival, and that curcumin may have anti‐ATL properties mediated, at least in part, by inhibiting Akt activity. We propose that Akt‐targeting agents could be useful for the treatment of ATL. In this regard, curcumin is a potentially promising compound for the treatment of ATL. (Cancer Sci 2006; 97: 322 – 327)

A modified version of galectin-9 suppresses cell growth and induces apoptosis of human T-cell leukemia virus type I-infected T-cell lines.

Retraction: The following article has been retracted through agreement between the first author and several coauthors, the journal Editor‐in‐Chief, Peter Lichter, and John Wiley & Sons, Ltd.: Okudaira T, Hirashima M, Ishikawa C, Makishi S, Tomita M, Matsuda T, Kawakami H, Taira N, Ohshiro K, Masuda M, Takasu N, Mori N. (2007). A modified version of galectin‐9 suppresses cell growth and induces apoptosis of human T‐cell leukemia virus type I‐infected T‐cell lines. Int J Cancer; 120 (May (10)): 2251‐2261, published online on 2 FEB 2007 in Wiley Online Library (www.onlinelibrary.wiley.com). After an investigation the retraction has been agreed due to inappropriate duplication of images and overlap with other published work.

NF-κB activation by Helicobacter pylori requires Akt-mediated phosphorylation of p65

BackgroundThe inflammatory response in Helicobacter pylori-infected gastric tissue is mediated by cag pathogenicity island (PAI)-dependent activation of nuclear factor-κB (NF-κB). Phosphatidylinositol 3-kinase (PI3K)/Akt signaling is known to play a role in NF-κB activation, but little information is available on the relationship between H. pylori and PI3K/Akt signaling in gastric epithelial cells. We examined whether H. pylori activates Akt in gastric epithelial cells, the role of cag PAI in this process and the role of Akt in regulating H. pylori-induced NF-κB activation.ResultsPhosphorylated Akt was detected in epithelial cells of H. pylori-positive gastric tissues. Although Akt was activated in MKN45 and AGS cells by coculture with cag PAI-positive H. pylori strains, a cag PAI-negative mutant showed no activation of Akt. H. pylori also induced p65 phosphorylation. PI3K inhibitor suppressed H. pylori-induced p65 phosphorylation and NF-κB transactivation, as well as interleukin-8 expression. Furthermore, transfection with a dominant-negative Akt inhibited H. pylori-induced NF-κB transactivation. Transfection with small interference RNAs for p65 and Akt also inhibited H. pylori-induced interleukin-8 expression.ConclusionThe results suggest that cag PAI-positive H. pylori activates Akt in gastric epithelial cells and this may contribute to H. pylori-mediated NF-κB activation associated with mucosal inflammation and carcinogenesis.

Transactivation of the CCL5/RANTES gene by Epstein-Barr virus latent membrane protein 1.

Retraction: The following article has been retracted through agreement between the first author and several coauthors, the journal Editor‐in‐Chief, Peter Lichter, and John Wiley & Sons, Ltd.: Uchihara JN, Krensky AM, Matsuda T, Kawakami H, Okudaira T, Masuda M, Ohta T, Takasu N, Mori N. (2006). Transactivation of the CCL5/RANTES gene by Epstein‐Barr virus latent membrane protein 1. Int J Cancer; 118 (February (5)): 747‐755 published online on 17 DEC 2004 in Wiley Online Library (www.onlinelibrary.wiley.com). After an investigation the retraction has been agreed due to inappropriate duplication of images and overlap with other published work.

Inhibition of heat shock protein-90 modulates multiple functions required for survival of human T-cell leukemia virus type I-infected T-cell lines and adult T-cell leukemia cells.

Retraction: The following article has been retracted through agreement between the first author and several coauthors, the journal Editor‐in‐Chief, Peter Lichter, and John Wiley & Sons, Ltd.: Kawakami H, Tomita M, Okudaira T, Ishikawa C, Matsuda T, Tanaka Y, Nakazato T, Taira N, Ohshiro K, Mori N. (2007). Inhibition of heat shock protein‐90 modulates multiple functions required for survival of human T‐cell leukemia virus type I‐infected T‐cell lines and adult T‐cell leukemia cells. Int J Cancer; 120 (April (8)): 1811‐1820, published online on 17 JAN 2007 in Wiley Online Library (www.onlinelibrary.wiley.com). After an investigation the retraction has been agreed due to inappropriate duplication of images and overlap with other published work.

Bisphosphonate incadronate inhibits growth of human T-cell leukaemia virus type I-infected T-cell lines and primary adult T-cell leukaemia cells by interfering with the mevalonate pathway

Anti‐resorptive bisphosphonates are used for the treatment of hypercalcaemia and bone complications associated with malignancies and osteoporosis, but also have been shown to have anti‐tumour effects in various cancers. Adult T‐cell leukaemia (ATL) is a fatal T‐cell malignancy caused by infection with human T‐cell leukaemia virus type I (HTLV‐I), and remains incurable. ATL is associated with osteolytic bone lesions and hypercalcaemia, both of which are major factors in the morbidity of ATL. Thus, the search for anti‐ATL agents that have both anti‐tumour and anti‐resorptive activity is warranted. The bisphosphonate agent, incadronate, prevented cell growth of HTLV‐I‐infected T‐cell lines and primary ATL cells, but not of non‐infected T‐cell lines or normal peripheral blood mononuclear cells. Incadronate induced S‐phase cell cycle arrest and apoptosis in HTLV‐I‐infected T‐cell lines, and treatment of these cells with substrates of the mevalonate pathway blocked the incadronate‐mediated growth suppression. Incadronate also prevented the prenylation of Rap1A protein. These results demonstrated that incadronate‐induced growth suppression occurs by interfering with the mevalonate pathway. Importantly, treatment with incadronate reduced tumour formation from an HTLV‐I‐infected T‐cell line when these cells were inoculated subcutaneously into severe combined immunodeficient mice. These findings suggest that incadronate could be potentially useful for the treatment of ATL.