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{"title"=>"Inhibition of Uterine sarcoma cell growth through suppression of endogenous tyrosine kinase B signaling", "type"=>"journal", "authors"=>[{"first_name"=>"Kenichi", "last_name"=>"Makino", "scopus_author_id"=>"56519161300"}, {"first_name"=>"Kazuhiro", "last_name"=>"Kawamura", "scopus_author_id"=>"7401690943"}, {"first_name"=>"Wataru", "last_name"=>"Sato", "scopus_author_id"=>"56233178600"}, {"first_name"=>"Nanami", "last_name"=>"Kawamura", "scopus_author_id"=>"22835249200"}, {"first_name"=>"Toshio", "last_name"=>"Fujimoto", "scopus_author_id"=>"35775248900"}, {"first_name"=>"Yukihiro", "last_name"=>"Terada", "scopus_author_id"=>"7202462833"}], "year"=>2012, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "pui"=>"365316181", "sgr"=>"84864248735", "doi"=>"10.1371/journal.pone.0041049", "scopus"=>"2-s2.0-84864248735", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "pmid"=>"22911740"}, "id"=>"91520d4b-8b60-3c42-8ea7-8881c5667072", "abstract"=>"Uterine leiomyosarcoma is an aggressive tumor typically found at advanced stages due to difficulties with early diagnosis. Because uterine leiomyosarcoma is resistant to conventional radiation and chemotherapy, the development of more potent medical therapeutics is anticipated. Using quantitative real-time RT-PCR and immunostaining, we found the expression of brain-derived neurotrophic factor (BDNF) and neurotropin-4/5, together with their receptor, tyrosine kinase B (TrkB), in different uterine sarcoma cell lines and primary tumor samples from uterine leiomyosarcoma patients. We noted that levels of BDNF were more abundant than those of neurotropin-4/5. Moreover, the expression of TrkB and its ligands was elevated in a multidrug-resistant cell line and samples obtained from patients with leiomyosarcoma. In cultured uterine sarcoma cells, inhibition of endogenous TrkB signaling by treatment with either the soluble TrkB ectodomain or the Trk receptor inhibitor, K252a, suppressed cell proliferation and increased apoptosis based on cell viability and proliferation, in situ terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end-labeling and caspase-3/7 assays, whereas an inactive plasma membrane nonpermeable K252b was ineffective. Correspondingly, treatment with exogenous BDNF increased cell proliferation. In in vivo studies in athymic nude mice bearing multidrug-resistant uterine sarcoma cell tumors, we demonstrate suppression of tumor growth by treatment with K252a, but not K252b, as reflected by decreased cell proliferation and increased levels of apoptosis and caspase-3/7 activities without obvious side effects. Our findings indicated that endogenous signaling of the TrkB pathway contributed to uterine sarcoma cell growth, and inhibition of TrkB signaling in these tumors could provide a novel medical therapy for patients with uterine sarcomas.", "link"=>"http://www.mendeley.com/research/inhibition-uterine-sarcoma-cell-growth-through-suppression-endogenous-tyrosine-kinase-b-signaling", "reader_count"=>11, "reader_count_by_academic_status"=>{"Researcher"=>2, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>4, "Student > Master"=>4}, "reader_count_by_user_role"=>{"Researcher"=>2, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>4, "Student > Master"=>4}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>1, "Agricultural and Biological Sciences"=>3, "Medicine and Dentistry"=>5, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Chemistry"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>5}, "Chemistry"=>{"Chemistry"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>3}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"Spain"=>1}, "group_count"=>0}

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• http://doi.org/10.1097/CAD.0b013e328364312f
• http://doi.org/10.3389/fonc.2015.00082
• http://doi.org/10.1016/j.bbcan.2015.03.003
• http://doi.org/10.13005/bpj/1755
• http://doi.org/10.1155/2015/243298
• http://doi.org/10.1016/j.canlet.2015.06.018
• http://doi.org/10.3892/etm.2017.4346
• http://doi.org/10.1590/0100-6991e-20192094
• http://doi.org/10.1073/pnas.1510194112
• http://doi.org/10.1371/journal.pone.0070616
• http://doi.org/10.3892/ol.2018.9854
• http://doi.org/10.1080/07357907.2020.1817481

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• 4632006
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• 4387920

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Figshare

• {"files"=>["https://ndownloader.figshare.com/files/315813", "https://ndownloader.figshare.com/files/315906"], "description"=>"<div><p>Uterine leiomyosarcoma is an aggressive tumor typically found at advanced stages due to difficulties with early diagnosis. Because uterine leiomyosarcoma is resistant to conventional radiation and chemotherapy, the development of more potent medical therapeutics is anticipated. Using quantitative real-time RT-PCR and immunostaining, we found the expression of brain-derived neurotrophic factor (BDNF) and neurotropin-4/5, together with their receptor, tyrosine kinase B (TrkB), in different uterine sarcoma cell lines and primary tumor samples from uterine leiomyosarcoma patients. We noted that levels of BDNF were more abundant than those of neurotropin-4/5. Moreover, the expression of TrkB and its ligands was elevated in a multidrug-resistant cell line and samples obtained from patients with leiomyosarcoma. In cultured uterine sarcoma cells, inhibition of endogenous TrkB signaling by treatment with either the soluble TrkB ectodomain or the Trk receptor inhibitor, K252a, suppressed cell proliferation and increased apoptosis based on cell viability and proliferation, <em>in situ</em> terminal deoxynucleotidyl transferase-mediated 2′-deoxyuridine 5′-triphosphate nick end-labeling and caspase-3/7 assays, whereas an inactive plasma membrane nonpermeable K252b was ineffective. Correspondingly, treatment with exogenous BDNF increased cell proliferation. In <em>in vivo</em> studies in athymic nude mice bearing multidrug-resistant uterine sarcoma cell tumors, we demonstrate suppression of tumor growth by treatment with K252a, but not K252b, as reflected by decreased cell proliferation and increased levels of apoptosis and caspase-3/7 activities without obvious side effects. Our findings indicated that endogenous signaling of the TrkB pathway contributed to uterine sarcoma cell growth, and inhibition of TrkB signaling in these tumors could provide a novel medical therapy for patients with uterine sarcomas.</p> </div>", "links"=>[], "tags"=>["inhibition", "uterine", "sarcoma", "suppression", "endogenous", "tyrosine", "kinase", "signaling"], "article_id"=>122344, "categories"=>["Cancer", "Molecular Biology", "Cell Biology"], "users"=>["Kenichi Makino", "Kazuhiro Kawamura", "Wataru Sato", "Nanami Kawamura", "Toshio Fujimoto", "Yukihiro Terada"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0041049.s001", "https://dx.doi.org/10.1371/journal.pone.0041049.s002"], "stats"=>{"downloads"=>2, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Inhibition_of_Uterine_Sarcoma_Cell_Growth_through_Suppression_of_Endogenous_Tyrosine_Kinase_B_Signaling/122344", "title"=>"Inhibition of Uterine Sarcoma Cell Growth through Suppression of Endogenous Tyrosine Kinase B Signaling", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-07-23 00:39:04"}
• {"files"=>["https://ndownloader.figshare.com/files/605531"], "description"=>"<p>MES-SA and MES-SA/Dx5 cells were cultured in medium alone or with different doses of BDNF. After incubation for 48 h, cell proliferation activity was measured by WST1 (n = 3). <i>Columns</i>, mean; <i>bars</i>, SE. *, <i>P</i><0.05 vs. control.</p>", "links"=>[], "tags"=>["proliferation", "uterine", "sarcoma"], "article_id"=>276020, "categories"=>["Cancer", "Molecular Biology", "Cell Biology"], "users"=>["Kenichi Makino", "Kazuhiro Kawamura", "Wataru Sato", "Nanami Kawamura", "Toshio Fujimoto", "Yukihiro Terada"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0041049.g004", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Promotion_of_cell_proliferation_in_uterine_sarcoma_cells_/276020", "title"=>"Promotion of cell proliferation in uterine sarcoma cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-23 01:40:20"}
• {"files"=>["https://ndownloader.figshare.com/files/605158"], "description"=>"<p>To compare the expression levels of TrkB (A), BDNF (B), NT4/5 (C) and galectin-1 (D) in human uterine myometrium (n = 8), leiomyoma (n = 8) and leiomyosarcoma (n = 7), quantitative real-time RT-PCR was performed. The expression level of each transcript was normalized using transcript levels of β-actin in the same samples. Nor, normal myometrium; Myo, leiomyoma; Sar, leiomyosarcoma. Same corresponding samples were indicated as closed circles. Results were represented by scatter diagrams. Horizontal lines indicate medians. *, <i>P</i><0.05. N.S, not significant.</p>", "links"=>[], "tags"=>["levels", "galectin-1", "uterine", "leiomyoma"], "article_id"=>275645, "categories"=>["Cancer", "Molecular Biology", "Cell Biology"], "users"=>["Kenichi Makino", "Kazuhiro Kawamura", "Wataru Sato", "Nanami Kawamura", "Toshio Fujimoto", "Yukihiro Terada"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0041049.g002", "stats"=>{"downloads"=>1, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Expression_levels_of_TrkB_BDNF_NT4_5_and_galectin_1_in_human_uterine_myometrium_leiomyoma_and_leiomyosarcoma_/275645", "title"=>"Expression levels of TrkB, BDNF, NT4/5 and galectin-1 in human uterine myometrium, leiomyoma and leiomyosarcoma.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-23 01:34:05"}
• {"files"=>["https://ndownloader.figshare.com/files/605716"], "description"=>"<p>(A) Time course of tumor growth in mice treated every 3 days with vehicle alone, K252a, or K252b (1 mg/kg, n = 6). Tumor volume on the first day of treatment was expressed as a relative tumor volume of 1. <i>Points</i>, mean; <i>bars</i>, SE. *, <i>P</i><0.05 vs. control. (B) Histological characterization of cell proliferation and apoptosis in tumors. In H&E staining of K252a-treated tumor tissue, the number of mitotic cells was decreased and cells with chromatin condensation (arrowhead) was increased. K252a treatment decreased Ki-67 signals and increased the number of TUNEL stained (green) nuclei. (Scale bars, 100 µm). (C) Caspase-3/7 activities in tumors. Samples were obtained from the mice bearing MES-SA/Dx5 tumors after 15 days of treatment. Data were standardized by protein concentrations, expressed as the fold increase relative to controls (vehicle alone), and normalized to 1. <i>Columns</i>, mean; <i>bars</i>, SE. *, <i>P</i><0.05 vs. control group.</p>", "links"=>[], "tags"=>["trk", "receptor", "inhibitor", "xenografts", "athymic", "nude"], "article_id"=>276203, "categories"=>["Cancer", "Molecular Biology", "Cell Biology"], "users"=>["Kenichi Makino", "Kazuhiro Kawamura", "Wataru Sato", "Nanami Kawamura", "Toshio Fujimoto", "Yukihiro Terada"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0041049.g005", "stats"=>{"downloads"=>1, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_Trk_receptor_inhibitor_on_in_vivo_tumor_growth_of_MES_SA_Dx5_xenografts_in_athymic_nude_mice_/276203", "title"=>"Effect of Trk receptor inhibitor on <i>in vivo</i> tumor growth of MES-SA/Dx5 xenografts in athymic nude mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-23 01:43:23"}
• {"files"=>["https://ndownloader.figshare.com/files/604995"], "description"=>"<p>(A) Messenger RNA expression of TrkB, p75NTR and their ligands was detected by RT-PCR in the uterine sarcoma cell lines, MES-SA and MES-SA/Dx5. As loading controls, the levels of β-actin were also assessed. The negative control lacked template DNA. (B) Messenger RNA expression of TrkB, p75NTR, and their ligands, BDNF and NT4/5, in surgical specimens from human uterine leiomyosarcomas was detected by RT-PCR. As loading controls, β-actin mRNA levels were assessed. (C) Expression levels of TrkB, BDNF and NT4/5 in uterine sarcoma cell lines were quantified by real-time RT-PCR. The expression level of each transcript was standardized using levels of β-actin transcripts in the same samples (n = 4). <i>Columns</i>, mean; <i>bars</i>, SE. *, <i>P</i><0.05 vs. MES-SA. (D) Immunohistochemical detection of TrkB, NT4/5 and BDNF proteins. Target proteins (red signal) were detected in MES-SA/Dx5 cells (Upper panels). Lower panels depict negative controls. Nuclei (blue) were stained with Hoechest 33342. (Scale bars, 50 µm).</p>", "links"=>[], "tags"=>["bdnf", "uterine", "sarcoma", "lines", "leiomyosarcoma"], "article_id"=>275478, "categories"=>["Cancer", "Molecular Biology", "Cell Biology"], "users"=>["Kenichi Makino", "Kazuhiro Kawamura", "Wataru Sato", "Nanami Kawamura", "Toshio Fujimoto", "Yukihiro Terada"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0041049.g001", "stats"=>{"downloads"=>2, "page_views"=>23, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Expression_of_TrkB_p75NTR_BDNF_and_NT4_5_in_uterine_sarcoma_cell_lines_and_human_uterine_leiomyosarcoma_tissues_/275478", "title"=>"Expression of TrkB, p75NTR, BDNF and NT4/5 in uterine sarcoma cell lines and human uterine leiomyosarcoma tissues.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-23 01:31:18"}
• {"files"=>["https://ndownloader.figshare.com/files/605390"], "description"=>"<p>To determine the effects of endogenous TrkB ligands on cell proliferation (A) and survival (B), uterine sarcoma cells (MES-SA/Dx5 cells) were cultured in medium alone (control, C), or with different doses of the TrkB ectodomain (TrkB EC), the pan-Trk inhibitor, K252a, or its inactive analogue, K252b. Cell proliferation activity was determined using the cell proliferation reagent WST1 after 48 h of culture, and cellular apoptosis was quantified using the caspase-3/7 assay after 8 h of culture (n = 3). <i>Columns</i>, mean; <i>bars</i>, SE. *, <i>P</i><0.05 vs. control. (C) DNA fragmentation was detected by <i>in situ</i> TUNEL staining. Nucleic acids are stained with propidium iodide (red). Representative images were obtained from MES-SA (upper panels) and MES-SA/Dx5 (lower panels) cells after treatment ± K252a (1 µM) or K252b (1 µM). The number of apoptotic cells (green) was increased in the cells with K252a treatment. (Scale bars, 100 µm).</p>", "links"=>[], "tags"=>["endogenous", "trkb", "ligands", "uteine", "sarcoma"], "article_id"=>275873, "categories"=>["Cancer", "Molecular Biology", "Cell Biology"], "users"=>["Kenichi Makino", "Kazuhiro Kawamura", "Wataru Sato", "Nanami Kawamura", "Toshio Fujimoto", "Yukihiro Terada"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0041049.g003", "stats"=>{"downloads"=>1, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Roles_of_endogenous_TrkB_ligands_in_in_vitro_growth_of_uteine_sarcoma_cells_/275873", "title"=>"Roles of endogenous TrkB ligands in <i>in vitro</i> growth of uteine sarcoma cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-23 01:37:53"}

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Relative Metric

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F1000Prime