Publications by authors named "Shunsuke Shimosaki"

11 Publications

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TAS-116 (pimitespib), a heat shock protein 90 inhibitor, shows efficacy in preclinical models of adult T-cell leukemia.

Cancer Sci 2021 Nov 18. Epub 2021 Nov 18.

Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.

Adult T-cell leukemia/lymphoma (ATL) is a highly chemoresistant malignancy of peripheral T lymphocytes caused by human T-cell leukemia virus type 1 infection, for which there is an urgent need for more effective therapeutic options. The molecular chaperone heat shock protein 90 (HSP90) plays a crucial role in nuclear factor-κB (NF-κB)-mediated antiapoptosis in ATL cells, and HSP90 inhibitors are new candidate therapeutics for ATL. Accordingly, we investigated the anti-ATL effects of a novel oral HSP90 inhibitor, TAS-116 (pimitespib), and the mechanisms involved in ex vivo and in vivo preclinical models. TAS-116 achieved IC values of less than 0.5 μmol/L in 10 ATL-related cell lines and less than 1 μmol/L in primary peripheral blood cells of nine ATL patients; no toxicity was observed toward CD4 lymphocytes from healthy donors, indicating the safety of this agent. Given orally, TAS-116 also showed significant inhibitory effects against tumor cell growth in ATL cell-xenografted mice. Furthermore, gene expression profiling of TAS-116-treated Tax-positive or -negative cell lines and primary ATL cells using DNA microarray and multiple pathway analysis revealed the significant downregulation of the NF-κB pathway in Tax-positive cells and cell-cycle arrest in Tax-negative cells and primary ATL cells. TAS-116 suppressed the activator protein-1 and tumor necrosis factor pathways in all examined cells. These findings strongly indicate the efficacy of TAS-116, regardless of the stage of ATL progression, and its potential application as a novel clinical anti-ATL therapeutic agent.
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http://dx.doi.org/10.1111/cas.15204DOI Listing
November 2021

Novel PRMT5-mediated arginine methylations of HSP90A are essential for maintenance of HSP90A function in NDRG2 ATL and various cancer cells.

Biochim Biophys Acta Mol Cell Res 2020 02 22;1867(2):118615. Epub 2019 Nov 22.

Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan. Electronic address:

N-myc downstream-regulated gene 2 (NDRG2) as a tumor suppressor is frequently downregulated in human T-lymphotropic retrovirus (HTLV-1)-infected adult T-cell leukemia (ATL) and variety of cancers, and negatively regulates PI3K signaling pathways through dephosphorylation of PTEN with protein phosphatase 2A (PP2A). We recently identified that protein arginine methyltransferase 5 (PRMT5) is one of novel NDRG2 binding proteins and the knockdown of PRMT5 induces cell apoptosis with degradation of several signaling molecules. To investigate how the apoptosis is induced by the knockdown PRMT5 expression, heat shock protein 90 alpha (HSP90A) was identified as a binding protein for NDRG2 or PRMT5 by immunoprecipitation-mass analysis. NDRG2/PP2A complex inhibited arginine methyltransferase activity of PRMT5 through dephosphorylation at Serine 335 (S335); however, in NDRG2 ATL-related cells, highly phosphorylated PRMT5 at S335 was mainly localized in cytoplasm with binding to HSP90A, resulting in enhancing arginine-methylation at the middle domain (R345 and R386). Since knockdown of PRMT5 expression or forced expression of HSP90A with alanine replacement of R345 or R386 induced apoptosis with the degradation of client proteins in NDRG2 ATL-related and other cancer cells, we here identified that the novel arginine methylations of HSP90A are essential for maintenance of its function in NDRG2 ATL and other cancer cells.
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http://dx.doi.org/10.1016/j.bbamcr.2019.118615DOI Listing
February 2020

Suppression of GPR56 expression by pyrrole-imidazole polyamide represents a novel therapeutic drug for AML with high EVI1 expression.

Sci Rep 2018 09 13;8(1):13741. Epub 2018 Sep 13.

Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.

G protein-coupled receptor 56 (GPR56) is highly expressed in acute myeloid leukemia (AML) cells with high EVI1 expression (EVI1 AML). Because GPR56 is a transcriptional target of EVI1 and silencing of GPR56 expression induces apoptosis, we developed a novel drug to suppress GPR56 expression in EVI1 AML cells. For this purpose, we generated pyrrole-imidazole (PI) polyamides specific to GPR56 (PIP/56-1 or PIP/56-2) as nuclease-resistant novel compounds that interfere with the binding of EVI1 to the GPR56 promoter in a sequence-specific manner. Treatment of EVI1 AML cell lines (UCSD/AML1 and Kasumi-3) with PIP/56-1 or PIP/56-2 effectively suppressed GPR56 expression by inhibiting binding of EVI1 to its promoter, leading to suppression of cell growth with increased rates of apoptosis. Moreover, intravenous administration of PIP/56-1 into immunodeficient Balb/c-RJ mice subcutaneously transplanted with UCSD/AML1 cells significantly inhibited tumor growth and extended survival. Furthermore, organ infiltration by leukemia cells in immunodeficient Balb/c-RJ mice, which were intravenously transplanted using UCSD/AML1 cells, was successfully inhibited by PIP/56-1 treatment with no apparent effects on murine hematopoietic cells. In addition, PIP treatment did not inhibit colony formation of human CD34 progenitor cells. Thus, PI polyamide targeting of GPR56 using our compound is promising, useful, and safe for the treatment of EVI1 AML.
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http://dx.doi.org/10.1038/s41598-018-32205-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6137133PMC
September 2018

Cell adhesion molecule-1 (CADM1) expressed on adult T-cell leukemia/lymphoma cells is not involved in the interaction with macrophages.

J Clin Exp Hematop 2017 Jul 18;57(1):15-20. Epub 2017 Apr 18.

Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University.

Cell adhesion molecule 1 (CADM1) is a cell adhesion molecule that is expressed in brain, liver, lung, testis, and some kinds of cancer cells including adult T-cell leukemia/lymphoma (ATLL). Recent studies have indicated the involvement of CADM1 in cell-cell contact between cytotoxic T-lymphocytes and virus infected cells. We previously reported that cell-cell interaction between lymphoma cells and macrophages induces lymphoma cell proliferation. In the present study, we investigated whether CADM1 is associated with cell-cell interaction between several human lymphoma cell lines and macrophages.CADM1 expression was observed in the ATLL cell lines, ATN-1, ATL-T, and ATL-35T, and in the B cell lymphoma cell lines, TL-1, DAUDI, and SLVL, using western blotting. Significant cell-cell interaction between macrophages and ATN-1, ATL-T, ATL-35T and MT-2, DAUDI, and SLVL cells, as assessed by induction of cell proliferation, was observed. Immunohistochemical analysis of human biopsy samples indicated CADM1 expression in 10 of 14 ATLL cases; however, no case of follicular lymphoma or diffuse large B-cell lymphoma was positive for CADM1. Finally, the interaction of macrophages with cells of the CADM1-negative ED ATLL cell line and CADM1-transfected ED cells was tested. However, significant cell-cell interaction between macrophage and CADM1-transfected ED cells was not observed. We conclude that CADM1 was not associated with cell-cell interaction between lymphoma cells and macrophages, although CADM1 may be a useful marker of ATLL for diagnostic procedures.
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http://dx.doi.org/10.3960/jslrt.17003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6144270PMC
July 2017

Development of a complete human IgG monoclonal antibody to transferrin receptor 1 targeted for adult T-cell leukemia/lymphoma.

Biochem Biophys Res Commun 2017 03 8;485(1):144-151. Epub 2017 Feb 8.

Division of Tumor and Cellular Biochemistry, Department of Medical Science, Faculty of Medicine, University of Miyazaki, Japan. Electronic address:

Iron is an essential nutrient for normal cell growth, and reprogramming of iron metabolism is essential to tumor cell survival and progression. HTLV-1-associated adult T-cell leukemia/lymphoma (ATLL) has no effective therapy and high levels of cell surface transferrin receptor 1 (TFR1) expression have been reported in ATLL by us and other groups. In this study, to develop a novel molecular-targeted therapy against TFR1 to modulate iron metabolism, we initially determined the expression pattern of several iron-related genes along with TFR1 and found that ATLL cells presented characteristic of an iron-deficiency state such as high expression of iron-regulatory protein 2 (IRP2) and low expression of its E3 ubiquitin-ligase, FBXL5. Therefore, we developed human IgG monoclonal antibodies to human TFR1 using a phage display method (ICOS method) to block the incorporation of the transferrin (TF)-iron complex into ATLL cells for inhibiting cell growth. One of the mAbs, JST-TFR09, presented its greater affinity to TFR1 on ATLL cells in flow cytometry (FCM) analysis than those of commercially available anti-TFR1 antibodies and identified high expression of TFR1 in most of the acute-type ATLL cells. Moreover, JST-TFR09 could interfere with binding between TFR1 and TF, which resulted in effective blockade of TFR1 internalization and induction of cell apoptosis by the treatment of ATLL cells with JST-TFR09. JST-TFR09 showed dual activities through direct cell cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC), and the treatment of JST-TFR09 significantly suppressed cell growth of ATLL cells with induction of apoptosis in in vitro and in vivo experiments. Thus, JST-TFR09 described here may become a promising therapeutic antibody for the treatment of ATLL.
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http://dx.doi.org/10.1016/j.bbrc.2017.02.039DOI Listing
March 2017

Development of a complete human anti-human transferrin receptor C antibody as a novel marker of oral dysplasia and oral cancer.

Cancer Med 2014 Aug 2;3(4):1085-99. Epub 2014 Jun 2.

Division of Oral and Maxillofacial Surgery, Medicine of Sensory and Motor Organs, University of Miyazaki, Miyazaki, Japan; Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.

Oral squamous cell carcinoma (OSCC) is the sixth most common cancer worldwide. Up to 20% of oral dysplasia cases have been suggested to undergo malignant transformation to OSCC; however, there are no methods to predict OSCC development. In this study, to identify the genes associated with oral dysplasia progression, we performed genomic copy number analyses of genomic DNA samples isolated from primary oral dysplasia and OSCC via the microdissection method and found elevated expression of transferrin receptor C (TfR1/TFRC) with genomic amplification in oral dysplasia and OSCC. The expression rate of TFRC in OSCC was significantly higher than that in dysplasia, suggesting that OSCC disease progression might be related to TFRC expression. Additionally, we investigated the in vitro and in vivo impacts of a newly established anti-human TFRC monoclonal antibody, which was isolated from a human cDNA library using the phage-display method, on cell proliferation and survival. The anti-TFRC antibody blocked the interaction between transferrin and TFRC and consequently inhibited iron uptake, leading to the iron deprivation-mediated suppression of cell growth and induction of apoptosis. Moreover, we demonstrated that the anti-TFRC antibody efficiently inhibited tumor growth in a murine xenograft OSCC model. Therefore, we suggest our developed complete human anti-human TFRC antibody as a useful, novel treatment for oral dysplasia and OSCC.
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http://dx.doi.org/10.1002/cam4.267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303177PMC
August 2014

Anti-allergic effect of the flavonoid myricitrin from Myrica rubra leaf extracts in vitro and in vivo.

Nat Prod Res 2011 Feb;25(4):374-80

Department of Cooperative Medical Research, Collaboration Center, Shimane University, Izumo, Japan.

Flavonoids are ingested by the general population as anti-oxidant and anti-inflammatory agents. In this study, we investigated the effects of myricitrin, a flavonoid rich in Myrica rubra leaf, upon anti-inflammatory action. Myrica rubra leaf extracts inhibited pro-inflammatory TNFα production in a macrophage cell line, Raw264.7 cells. We observed that the serum IgE levels in the leaf extract-treated DO11.10, a mouse allergy model, were down-regulated. HPLC was performed to demonstrate that M. rubra leaf extracts contain a large amount of myricitrin. We observed an inhibitory effect of HPLC-purified myricitrin on TNFα production in Raw264.7 cells. Thus, myricitrin may be of potential interest in the management of inflammatory conditions.
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http://dx.doi.org/10.1080/14786411003774320DOI Listing
February 2011

The ubiquitin-like protein monoclonal nonspecific suppressor factor beta conjugates to endophilin II and regulates phagocytosis.

FEBS J 2009 Nov 1;276(21):6355-63. Epub 2009 Oct 1.

Department of Cooperative Medical Research, Collaboration Center, Shimane University, Izumo 693-8501, Japan.

Monoclonal nonspecific suppressor factor beta (MNSFbeta) is a ubiquitously expressed member of the ubiquitin-like family that has been implicated in various biological functions. Previous studies have demonstrated that MNSFbeta covalently binds to the intracellular proapoptotic protein Bcl-G in cells of the macrophage cell line Raw264.7, suggesting involvement of this ubiquitin-like protein in apoptosis. In this study, we purified a 62 kDa MNSFbeta adduct from murine liver lysates by sequential chromatography on DEAE and anti-MNSFbeta IgG-conjugated Sepharose. MALDI-TOF MS fingerprinting revealed that this MNSFbeta adduct consists of an 8.5 kDa MNSFbeta and endophilin II, a member of the endophilin A family. MNSFbeta may conjugate to endophilin II with a linkage between the C-terminal Gly74 and Lys294. We confirmed this result by immunoprecipitation/western blot studies. Endophilin II was ubiquitously expressed in various tissues, although a truncated form was observed in liver. The 62 kDa MNSFbeta-endophilin II was specifically expressed in liver and macrophages. Small interfering RNA-mediated knockdown of endophilin II and/or MNSFbeta promoted phagocytosis of zymosan in Raw264.7 cells. Conversely, cotransfection of endophilin II and MNSFbeta cDNAs inhibited the phagocytosis of zymosan. Such inhibition was not observed in cells expressing a mutant of endophilin II in which Lys294 was replaced by arginine. These results suggest that the post-translational modification of endophilin II by MNSFbeta might be implicated in phagocytosis by macrophages.
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http://dx.doi.org/10.1111/j.1742-4658.2009.07348.xDOI Listing
November 2009

Seed-specific expression of truncated OsGAD2 produces GABA-enriched rice grains that influence a decrease in blood pressure in spontaneously hypertensive rats.

Transgenic Res 2009 Dec 12;18(6):865-76. Epub 2009 May 12.

Department of Biological Science, Shimane University, Nishikawatsu 1060, Matsue, Shimane 690-8504, Japan.

Gamma-aminobutyric acid (GABA) is a four-carbon amino acid that is commonly present in living organisms and functions as a major inhibitory neurotransmitter in mammals. It is understood to have a potentially anti-hypertensive effect in mammals. GABA is synthesized from glutamate by glutamate decarboxylase (GAD). In plants, GAD is regulated via its calmodulin-binding domain (CaMBD) by Ca(2+)/CaM. We have previously reported that a C-terminal truncated version of one of the five rice GAD isoforms, GAD2DeltaC, revealed higher enzymatic activity in vitro and that its over-expression resulted in exceptionally high GABA accumulation (Akama and Takaiwa, J Exp Bot 58:2699-2607, 2007). In this study, GAD2DeltaC, under the control of the rice glutelin promoter (GluB-1), was introduced into rice cells via Agrobacterium-mediated transformation to produce transgenic rice lines. Analysis of the free amino acid content of rice grains revealed up to about a 30-fold higher level of GABA than in non-transformed rice grains. There were also very high levels of various free protein amino acids in the seeds. GABA-enriched rice grains were milled to a fine powder for oral administration to spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto rats (WKYs). Six weeks of administration showed that transgenic rice brings about a 20 mmHg decrease in blood pressure in two different kinds of SHRs, while there was no significant hypotensive effect in WKYs. These results suggest an alternative way to control and/or cure hypertension in humans with GABA-enriched rice as part of a common daily diet.
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http://dx.doi.org/10.1007/s11248-009-9272-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2776163PMC
December 2009

Evaluation of bedding and nesting materials for laboratory mice by preference tests.

Exp Anim 2007 Oct;56(5):363-8

Department of Experimental Animals, Center for Integrated Research in Science, Faculty of Medicine, Shimane University, Izumo, Japan.

Bedding and nesting materials can improve the health and environmental welfare of laboratory mice. This study was carried out to examine which items are actually preferred by mice. Two series of studies were performed on four types of floor-covering materials (Wood-shavings (Clean-chip), Cloth (Agrebe), Recycled-paper (Paper-clean), Paper (Care-feeaz), and on four types of nesting materials (Recycled-paper (Shepherd-shack), Cloth (Agrebe), Wood (Wood-cylinder), and Polycarbonate (Mouse-igloo). Preference of bedding materials was judged by the time length of staying in a cage. The results indicate that mice stayed in the cloth material (Agrebe) longer than in other bedding materials (light 51.1 +/- 5.3%, dark 51.5 +/- 2.6%). In the second experiment, the duration of stay in Agrebe was significantly longer than that in the other nesting materials in the light phase (70.9 +/- 2.4%). In the dark phase, staying time both in Agrebe and Shepherd-shack were significantly longer. These data suggest that cloth bedding and nesting is recommended for the environmental enrichment of laboratory mice.
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http://dx.doi.org/10.1538/expanim.56.363DOI Listing
October 2007
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