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Taeko Okudaira

Publications and source records attributed to Taeko Okudaira.

15 recordsLinked to original sources
PubMed2007

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.

The molecular chaperone Hsp90 is involved in the stabilization and conformational maturation of many signaling proteins that are deregulated in cancers. The geldanamycin derivative 17-AAG is currently tested in clinical trials and known to inhibit the function of Hsp90 and promote the proteasomal degradation of its misfolded client proteins. ATL is a fatal malignancy of T lymphocytes caused by HTLV-I infection and remains incurable. Since Hsp90 is overexpressed in HTLV-I-infected T-cell lines and primary ATL cells, we analyzed the effects of 17-AAG on cell survival, apoptosis and expression of signal transduction proteins. HTLV-I-infected T-cell lines and primary ATL cells were significantly more sensitive to 17-AAG in cell survival assays than normal PBMCs. 17-AAG induced the inhibition of cell cycle and apoptosis. These effects could be mediated by inactivation of NF-kappaB, AP-1 and PI3K/Akt pathways, as well as reduction of expression of proteins involved in the G1-S cell cycle transition and apoptosis. Proteasome inhibition interfered with 17-AAG-mediated signaling proteins depletion. Collectively, our results indicate that 17-AAG suppresses ATL cell survival through, at least in part, destabilization of several client proteins and suggest that 17-AAG is a potentially useful chemotherapeutic agent for ATL.

Adult↗
PubMed2006

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.

BACKGROUND: Human 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. RESULTS: Constitutive 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. CONCLUSION: Our 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.

Base Sequence↗
PubMed2006

Transactivation of the ICAM-1 gene by CD30 in Hodgkin's lymphoma.

The ICAM-1/LFA-1 complex mediates cell-cell interaction. ICAM-1 is overexpressed in Hodgkin/Reed-Sternberg (H/RS) cells, and serum levels of its soluble form are higher in Hodgkin's lymphoma (HL) patients than in controls. There are no data, however, regarding the regulation of expression of ICAM-1 in H/RS cells. CD30 was identified in H/RS cells of HL and has attracted much interest as a molecular marker of HL. To analyze ICAM-1 expression in H/RS cells, we examined the expression of ICAM-1, LFA-1, CD30 and CD30L in HL-derived cell lines. All cell lines expressed ICAM-1 and CD30, but not LFA-1 or CD30L. CD30 induced ICAM-1 expression. Analysis of the ICAM-1 promoter showed the importance of NF-kappaB binding site for CD30-induced ICAM-1 gene expression. Coexpression of IkappaB, IKK, NIK and TRAF dominant-negative constructs with CD30 inhibited CD30-induced activation of ICAM-1 promoter, suggesting that CD30 induces ICAM-1 via NF-kappaB signalling. The ICAM-1 promoter was activated by the C-terminal region of CD30, which activated NF-kappaB signalling. A decoy CD30 lacking the cytoplasmic region inhibited ICAM-1 promoter activity in HL cell lines. Thus, in H/RS cells, ligand-independent activation of CD30 signalling activates NF-kappaB and this leads to constitutive ICAM-1 expression, suggesting a link between 2 well known phenotypic characteristics of HL, CD30 and ICAM-1 overexpression.

Antigens, CD↗
PubMed2006

Curcumin (diferuloylmethane) inhibits constitutive active NF-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.

Adult T-cell leukemia (ATL) is a fatal malignancy of T lymphocytes caused by infection with human T-cell leukemia virus type I (HTLV-I) and remains incurable. Curcumin (diferuloylmethane), the major pigment of the spice turmeric, can be potentially effective by promoting cell apoptosis. Here we examined whether curcumin is effective in the treatment of ATL. Curcumin prevented cell growth of HTLV-I-infected T-cell lines and primary ATL cells but not of normal peripheral blood mononuclear cells. Curcumin induced cell cycle arrest by reducing the expression of cyclin D1, Cdk1 and Cdc25C and apoptosis by reducing the expression of XIAP and survivin. Most of these genes are known to be regulated by NF-kappaB, which plays a critical role in oncogenesis by HTLV-I. Curcumin suppressed constitutive active NF-kappaB of HTLV-I-infected T-cell lines and primary ATL cells by inhibiting phosphorylation of IkappaBalpha. Curcumin also inhibited Tax-induced NF-kappaB transcriptional activity. However, curcumin-induced suppression of cell growth did not correlate with Tax expression level. Curcumin inhibited the growth of HTLV-I-infected T-cell tumors implanted subcutaneously in SCID mice. Our results indicate that curcumin has tumor-suppressive activity against ATL.

Adult↗
PubMed2006

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)-3beta, 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-3beta. 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.

Antineoplastic Agents↗
PubMed2006

Transactivation of CCL20 gene by Epstein-Barr virus latent membrane protein 1.

CCL20 is expected to play a crucial role in the initiation of immune responses and tumour growth. However, expression of CCL20 in Epstein-Barr virus (EBV)-associated diseases has not been studied. We examined the contribution of EBV infection and EBV-encoded latent membrane protein (LMP)-1 to CCL20 expression. EBV infection and LMP-1 induced CCL20 mRNA expression in the EBV-negative Burkitt lymphoma (BL) cell lines and the embryonic kidney cell line. Histone deacetylase inhibitor-stimulated endogenous LMP-1 also induced CCL20 expression in an EBV-positive BL cell line. Analysis of the CCL20 promoter showed that it was activated by LMP-1 C-terminal activation region (CTAR)-1 and CTAR-2. Co-expression of IkappaB alpha, IkappaB beta, IkappaB kinase (IKK)alpha, IKKbeta, IKKgamma, nuclear factor (NF)-kappaB-inducing kinase and tumour necrosis factor receptor-associated factor 2 dominant-negative constructs with LMP-1 inhibited the activation of the CCL20 promoter by LMP-1, suggesting that LMP-1 induces CCL20 via NF-kappaB signalling. The requirement for the NF-kappaB-binding site in the CCL20 promoter in LMP-1 responsiveness was established. Our results indicate that activation of the NF-kappaB pathway by LMP-1 is required for the activation of CCL20 expression.

Burkitt Lymphoma↗
PubMed2006

NIK-333 inhibits growth of human T-cell leukemia virus type I-infected T-cell lines and adult T-cell leukemia cells in association with blockade of nuclear factor-kappaB signal pathway.

Adult T-cell leukemia (ATL) is caused by human T-cell leukemia virus type I (HTLV-I) and remains incurable. NIK-333, a novel synthetic retinoid, prevents the recurrence of human hepatoma after surgical resection of primary tumors. We explored the effects of NIK-333 on HTLV-I-infected T-cell lines and ATL cells. NIK-333 inhibited cell proliferation, induced G1 arrest, and resulted in massive apoptosis in all tested HTLV-I-infected T-cell lines and ATL cells, whereas little effect was observed on normal peripheral blood mononuclear cells. NIK-333 treatment decreases the levels of cyclin D1, cyclin D2, cIAP2, and XIAP proteins. Further analysis showed that NIK-333 inactivated nuclear factor-kappaB in HTLV-I-infected T-cell lines. In animal studies, treatment with NIK-333 (100 mg/kg given orally every other day) produced partial inhibition of growth of tumors of a HTLV-I-infected T-cell line transplanted s.c. in severe combined immunodeficient mice. Our results indicate that NIK-333 is a potentially useful therapeutic agent for patients with ATL.

Animals↗
PubMed2005

Curcumin suppresses constitutive activation of AP-1 by downregulation of JunD protein in HTLV-1-infected T-cell lines.

Activation of the activator protein 1 (AP-1) plays a critical role in oncogenesis by human T-cell leukemia virus type 1 (HTLV-1), the etiologic agent of adult T-cell leukemia (ATL), and is required for maintenance of the malignant phenotype. Curcumin (diferuloylmethane), the major pigment of the spice turmeric, has anti-tumor activity; however, the effect of curcumin against ATL has not been elucidated. In this study, we examined the effects of curcumin on AP-1 activity in HTLV-1-infected T-cell lines. Curcumin suppressed the constitutive AP-1 DNA-binding and transcriptional activity in HTLV-1-infected T-cell line. Curcumin also inhibited HTLV-1 Tax-induced AP-1 transcriptional activity. JunD was detectable as a major component of the AP-1-DNA complex in HTLV-1-infected T-cell lines using the supershift assay. The expression of JunD was suppressed by curcumin treatment. Curcumin inhibited the growth of HTLV-1-infected T-cell lines by inducing cell cycle arrest followed by apoptosis. Our results suggest that suppression of the constitutively active AP-1 by curcumin is due to, at least in-part, reducing the expression of JunD by curcumin. Inhibition of AP-1 activity by curcumin may be one of the mechanisms responsible for the anti-ATL effect of curcumin. We propose that curcumin is a potentially promising compound for the treatment of ATL.

Apoptosis↗
PubMed2005

Human T cell leukemia virus type I-infected patients with Hashimoto's thyroiditis and Graves' disease.

CONTEXT: Autoimmune thyroid diseases have been reported to be associated with human T cell leukemia virus type I (HTLV-I) infection. HTLV-I proviral load is related to the development of HTLV-I-associated myelopathy/tropical spastic paraparesis and has also been shown to be elevated in the peripheral blood of HTLV-I-infected patients with uveitis, arthritis, and connective tissue disease. OBJECTIVE: The objective of the study was to evaluate the proviral load in HTLV-I-infected patients with Hashimoto's thyroiditis (HT) or Graves' disease (GD) and ascertain the ability of HTLV-I to infect thyroid cells. PATIENTS AND METHODS: A quantitative real-time PCR assay was developed to measure the proviral load of HTLV-I in peripheral blood mononuclear cells from 26 HTLV-I-infected patients with HT, eight HTLV-I-infected patients with GD, or 38 asymptomatic HTLV-I carriers. Rat FRTL-5 thyroid cells were cocultured with HTLV-I-infected T cell line MT-2 or uninfected T cell line CCRF-CEM. After coculture with T cell lines, changes in Tax and cytokine mRNA expression were studied by RT-PCR. RESULTS: HTLV-I proviral load was significantly higher in the peripheral blood of patients with HT and GD than asymptomatic HTLV-I carriers. In the peripheral blood from HTLV-I-infected patients with HT, HTLV-I proviral load did not correlate with the thyroid peroxidase antibody or thyroglobulin antibody titer. After coculture with MT-2 cells, FRTL-5 cells expressed HTLV-I-specific Tax mRNA. These cocultured FRTL-5 cells with MT-2 cells expressed IL-6 mRNA and proliferated more actively than those cocultured with CCRF-CEM cells. CONCLUSION: Our findings suggest the role of the retrovirus in the development of autoimmune thyroid diseases in HTLV-I-infected patients.

Adult↗
PubMed2005

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

Chemokines and chemokine receptors mediate lymphocyte migration and tissue localization. To analyze CCL5 (RANTES) expression by EBV-infected cells, we examined the expression of CCL5 in BL cell lines. Among 4 BL cell lines, those infected with EBV selectively expressed the CCL5 gene and secreted CCL5. Four cell lines also expressed CCR5, a receptor for CCL5. EBV-encoded LMP-1, a pleiotropic protein that effects gene expression, cell transformation, growth and death, induces expression of CCL5 mRNA and secretion of CCL5 in the EBV-negative BL cell line BJAB and the embryonic kidney cell line 293T. HDACI-stimulated endogenous LMP-1 also induced CCL5 expression in an EBV-positive BL cell line. Analysis of the CCL5 promoter revealed that it is activated by both LMP-1 C-terminal activation domains, CTAR-1 and CTAR-2, which can activate NF-kappaB signaling. Coexpression of IkappaBalpha, IkappaBbeta, IKKalpha, IKKbeta, NIK and TRAF2 dominant-negative constructs, with LMP-1 inhibited the activation of the CCL5 promoter by LMP-1, suggesting that LMP-1 induces CCL5 via NF-kappaB signaling. The NF-kappaB binding sites, R(A/B), located at positions -71 to -43 relative to the putative transcription start site in the CCL5 promoter, were essential for the activation of CCL5 gene expression by LMP-1. These results indicate that the activation of the NF-kappaB pathway by LMP-1 is required for the activation of CCL5 expression.

Binding Sites↗
PubMed2004

Childhood blastic NK cell leukemia successfully treated with L-asparagenase and allogeneic bone marrow transplantation.

Blastic NK cell lymphoma/leukemia is a rare and highly malignant neoplasia in both adults and children. It is characterized by lymphoblastoid morphology without cytoplasmic granules and immature NK cell immunophenotypes (CD56+, CD57-, CD16-). It has predilection for extranodal organ involvement, and the prognosis of affected patients is extremely poor under the current chemotherapy. We present a 14-year-old girl who was diagnosed as having blastic NK cell leukemia with mediastinal, pleural, and pericardial involvement. Immunophenotyping of her leukemic cells showed positive for CD2, CD5, CD7, CD34, CD56, HLA-DR, and cytoplasmic CD3. T cell receptor (TCR) and Immunoglobulin heavy chain genes were not rearranged. She received chemotherapy for acute lymphoblastic leukemia incorporating L-asparaginase (L-asp) which successfully induced complete remission. Bone marrow transplantation (BMT) from her HLA-identical sibling was conducted after two courses of consolidation therapy. Expression of aspargine synthetase (AS) protein in the leukemic cells at diagnosis was examined by an immunocytochemical method. She remains in hematological remission for over 36 months after BMT. The expression of AS protein was negative, suggesting that the leukemic cells were sensitive to L-asp. Induction and consolidation therapy incorporating L-asp followed by allo-BMT might be a promising treatment for child hood blastic NK cell leukemia, but more samples of the rare leukemia need to be studied before any definitive conclusions can be drawn.

Adolescent↗
PubMed2003

Severe infusion reaction induced by trastuzumab: a case report.

We report a case of a severe infusion reaction caused by trastuzumab. A 59-year-old woman with metastatic breast cancer was treated with trastuzumab. During the first infusion, initial symptoms such as severe headache and general fatigue developed. Blood pressure fell 90 minutes after these initial symptoms. A collapsed lung was demonstrated by chest X-ray and computed tomography. Steroid therapy was successfully used for these reactions. Careful monitoring of vital signs, examination of the respiratory system, and the use of steroids are recommended for severe infusion reaction.

Anaphylaxis↗
PubMed2002

[Pancreatic islet cell carcinoma with multiple hepatic metastases successfully treated with a streptozocin/5-FU regimen--a case report].

A 53-year-old woman was hospitalized because of lientery and steatorrhea. CT scans revealed a pancreatic head tumor along with multiple liver tumors. The pancreatic head tumor had spread to the duodenum. Following tumor biopsy with gastrointestinal fiberscopy, we diagnosed a pancreatic malignant islet cell tumor with multiple liver metastases. Since there was no clinical evidence of recognized endocrinopathy, we diagnosed "nonfunctioning" tumor. At first we administered only 5-FU at a dose of 370 mg/m2/day continuously for two weeks. However, neither the pancreatic head tumor nor the metastatic liver tumors changed in size. We then administered streptozocin and 5-FU at doses of 1,000 mg/m2 and 370 mg/m2, respectively, every week. The patient received a total of 10 g/m2 of streptozocin. After this treatment, the enlarged metastatic liver tumors were reduced in size, with marked improvement in liver enzyme. Toxic reactions to this regimen were mild. Only grade 1 nausea and alopecia were observed during the treatment. No hematological toxicity was observed, nor, with sufficient diuresis, was nephrotoxicity, demonstrating that this regimen can be administered safely.

Antineoplastic Combined Chemotherapy Protocols↗