サンペトラ, オルテア (サンペトラ, オルテア)

Sampetrean, Oltea

写真a

所属(所属キャンパス)

医学部 先端医科学研究所(遺伝子制御研究部門) (信濃町)

職名

助教(有期)

 

研究分野 【 表示 / 非表示

  • 細胞生物学

  • 脳神経外科学

研究キーワード 【 表示 / 非表示

  • 悪性グリオーマ

  • 脳腫瘍

研究テーマ 【 表示 / 非表示

  • 悪性脳腫瘍幹細胞の特性の解明, 

    2009年04月
    -
    継続中

 

論文 【 表示 / 非表示

  • CD44 variant inhibits insulin secretion in pancreatic β cells by attenuating LAT1-mediated amino acid uptake

    Kobayashi N., Okazaki S., Sampetrean O., Irie J., Itoh H., Saya H.

    Scientific Reports (Scientific Reports)  8 ( 1 )  2018年12月

     概要を見る

    © 2018 The Author(s). CD44 variant (CD44v) contributes to cancer stemness by stabilizing the xCT subunit of system xc(-) and thereby promoting its glutamate-cystine antiporter activity. CD44 has also been implicated in autoimmune insulitis and inflammation in diabetic islets, but whether CD44v regulates insulin secretion has remained unclear. Here we show that CD44v inhibits insulin secretion by attenuating amino acid transport mediated by the L-type amino acid transporter LAT1. CD44v expression level was inversely related to insulin content in islets of normal and diabetic model mice. Knockdown of CD44 increased insulin secretion, the intracellular insulin level, and the transport of neutral amino acids mediated by LAT1 in Min6 cells. Attenuation of the uptake of neutral amino acids with a LAT inhibitor reduced insulin secretion and insulin content in Min6 cells, whereas overexpression of LAT1 increased insulin secretion. Moreover, inhibition of LAT1 prevented the increase in insulin secretion and content induced by CD44 depletion in Min6 cells. Our results thus implicate CD44v in the regulation of insulin secretion and reveal that amino acid transport is rate limiting for such secretion. They further suggest that amino acid transport mediated by LAT1 is a potential therapeutic target for diabetes.

  • Gold-nanofève surface-enhanced Raman spectroscopy visualizes hypotaurine as a robust anti-oxidant consumed in cancer survival

    Shiota M., Naya M., Yamamoto T., Hishiki T., Tani T., Takahashi H., Kubo A., Koike D., Itoh M., Ohmura M., Kabe Y., Sugiura Y., Hiraoka N., Morikawa T., Takubo K., Suina K., Nagashima H., Sampetrean O., Nagano O., Saya H., Yamazoe S., Watanabe H., Suematsu M.

    Nature Communications (Nature Communications)  9 ( 1 )  2018年12月

     概要を見る

    © 2018 The Author(s). Gold deposition with diagonal angle towards boehmite-based nanostructure creates random arrays of horse-bean-shaped nanostructures named gold-nanofève (GNF). GNF generates many electromagnetic hotspots as surface-enhanced Raman spectroscopy (SERS) excitation sources, and enables large-area visualization of molecular vibration fingerprints of metabolites in human cancer xenografts in livers of immunodeficient mice with sufficient sensitivity and uniformity. Differential screening of GNF-SERS signals in tumours and those in parenchyma demarcated tumour boundaries in liver tissues. Furthermore, GNF-SERS combined with quantum chemical calculation identified cysteine-derived glutathione and hypotaurine (HT) as tumour-dominant and parenchyma-dominant metabolites, respectively. CD44 knockdown in cancer diminished glutathione, but not HT in tumours. Mechanisms whereby tumours sustained HT under CD44-knockdown conditions include upregulation of PHGDH, PSAT1 and PSPH that drove glycolysis-dependent activation of serine/glycine-cleavage systems to provide one-methyl group for HT synthesis. HT was rapidly converted into taurine in cancer cells, suggesting that HT is a robust anti-oxidant for their survival under glutathione-suppressed conditions.

  • Tranilast inhibits the expression of genes related to epithelial-mesenchymal transition and angiogenesis in neurofibromin-deficient cells

    Harigai R., Sakai S., Nobusue H., Hirose C., Sampetrean O., Minami N., Hata Y., Kasama T., Hirose T., Takenouchi T., Kosaki K., Kishi K., Saya H., Arima Y.

    Scientific Reports (Scientific Reports)  8 ( 1 )  2018年12月

     概要を見る

    © 2018 The Author(s). Neurofibromatosis type 1 (NF1) is caused by germline mutations in the NF1 gene and is characterized by café au lait spots and benign tumours known as neurofibromas. NF1 encodes the tumour suppressor protein neurofibromin, which negatively regulates the small GTPase Ras, with the constitutive activation of Ras signalling resulting from NF1 mutations being thought to underlie neurofibroma development. We previously showed that knockdown of neurofibromin triggers epithelial-mesenchymal transition (EMT) signalling and that such signalling is activated in NF1-associated neurofibromas. With the use of a cell-based drug screening assay, we have now identified the antiallergy drug tranilast (N-(3,4-dimethoxycinnamoyl) anthranilic acid) as an inhibitor of EMT and found that it attenuated the expression of mesenchymal markers and angiogenesis-related genes in NF1-mutated sNF96.2 cells and in neurofibroma cells from NF1 patients. Tranilast also suppressed the proliferation of neurofibromin-deficient cells in vitro more effectively than it did that of intact cells. In addition, tranilast inhibited sNF96.2 cell migration and proliferation in vivo. Knockdown of type III collagen (COL3A1) also suppressed the proliferation of neurofibroma cells, whereas expression of COL3A1 and SOX2 was increased in tranilast-resistant cells, suggesting that COL3A1 and the transcription factor SOX2 might contribute to the development of tranilast resistance.

  • Epidermal growth factor receptor promotes glioma progression by regulating xCT and GluN2B-containing N-methyl-d-aspartate–sensitive glutamate receptor signaling

    Suina K., Tsuchihashi K., Yamasaki J., Kamenori S., Shintani S., Hirata Y., Okazaki S., Sampetrean O., Baba E., Akashi K., Mitsuishi Y., Takahashi F., Takahashi K., Saya H., Nagano O.

    Cancer Science (Cancer Science)  109 ( 12 ) 3874 - 3882 2018年12月

    ISSN  13479032

     概要を見る

    © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. Autocrine and paracrine factors, including glutamate and epidermal growth factor (EGF), are potent inducers of brain tumor cell invasion, a pathological hallmark of malignant gliomas. System xc(–) consists of xCT and CD98hc subunits and functions as a plasma membrane antiporter for the uptake of extracellular cystine in exchange for intracellular glutamate. We previously showed that the EGF receptor (EGFR) interacts with xCT and thereby promotes the activity of system xc(–) in a kinase-independent manner, resulting in enhanced glutamate release in glioma cells. However, the molecular mechanism underlying EGFR-mediated glioma progression in a glutamate-rich microenvironment has remained unclear. Here we show that the GluN2B subunit of the N-methyl-d-aspartate–sensitive glutamate receptor (NMDAR) is a substrate of EGFR in glioma cells. In response to EGF stimulation, EGFR phosphorylated the COOH-terminal domain of GluN2B and thereby enhanced glutamate-NMDAR signaling and consequent cell migration in EGFR-overexpressing glioma cells. Treatment with the NMDAR inhibitor MK-801 or the system xc(–) inhibitor sulfasalazine suppressed EGF-elicited glioma cell migration. The administration of sulfasalazine and MK-801 also synergistically suppressed the growth of subcutaneous tumors formed by EGFR-overexpressing glioma cells. Furthermore, shRNA-mediated knockdown of xCT and GluN2B cooperatively prolonged the survival of mice injected intracerebrally with such glioma cells. Our findings thus establish a central role for EGFR in the signaling crosstalk between xCT and GluN2B-containing NMDAR in glioma cells.

  • HER2 heterogeneity is associated with poor survival in HER2-positive breast cancer

    Hosonaga M., Arima Y., Sampetrean O., Komura D., Koya I., Sasaki T., Sato E., Okano H., Kudoh J., Ishikawa S., Saya H., Ishikawa T.

    International Journal of Molecular Sciences (International Journal of Molecular Sciences)  19 ( 8 )  2018年08月

    ISSN  16616596

     概要を見る

    © 2018 by the authors. Licensee MDPI, Basel, Switzerland. Intratumoral human epidermal growth factor receptor 2 (HER2) heterogeneity has been reported in 16–36% of HER2-positive breast cancer and its clinical impact is under discussion. We examined the biological effects of HER2-heterogeneity on mouse models and analyzed metastatic brains by RNA sequence analysis. A metastatic mouse model was developed using 231-Luc (triple negative cells) and 2 HER2-positive cell lines, namely, HER2-60 and HER2-90 which showed heterogeneous and monotonous HER2 expressions, respectively. Metastatic lesions developed in 3 weeks in all the mice injected with HER2-60 cells, and in 69% of the mice injected with HER2-90 and 87.5% of the mice injected with 231-Luc. The median survival days of mice injected with 231-Luc, HER2-60, and HER2-90 cells were 29 (n = 24), 24 (n = 22) and 30 (n = 13) days, respectively. RNA sequence analysis showed that CASP-1 and its related genes were significantly downregulated in metastatic brain tumors with HER2-60 cells. The low expression of caspase-1 could be a new prognostic biomarker for early relapse in HER2-positive breast cancer.

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  • グリオーマ幹細胞が形成するニッチの成立機構解明と阻害方法の確立

    2019年04月
    -
    2022年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, サンペトラ オルテア, 基盤研究(C), 補助金,  代表

  • グリオーマ幹細胞のニッチ特性の解明とそれを標的とした治療戦略の考案

    2016年04月
    -
    2019年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, サンペトラ, オルテア, 基盤研究(C), 補助金,  代表